case study about viruses

12 microscopic discoveries that went 'viral' in 2022

Twelve recent studies showcase how viruses affect humans and other organisms all across the globe.

Viruses have been a near-constant subject of headline news in recent years, especially since the COVID-19 pandemic began. But of course, the pathogens' influence stretches back to the start of human history and beyond — in fact, viruses have had a hand in shaping the trajectory of all life on Earth. In 2022, these 13 "viral" stories highlighted just a few ways the pathogens affect the human body and the world at large. 

1. 'Zombie' viruses in Siberian permafrost reawakened 

Scientists recently isolated never-before-seen viruses from Siberian permafrost and rivers, as well as preserved mammoth wool and an ancient wolf's intestines. The team thawed out these viruses and determined that some of them could still infect amoeba, despite being up to 48,000 years old. Although the newly described viruses can't infect humans, other viruses lurking in permafrost — and now defrosting due to climate change — theoretically could. 

2. Cold sore virus spread thanks to smooching 

The virus behind cold sores, herpes simplex virus 1 (HSV-1), likely gained prominence about 5,200 years ago, possibly due to the rising popularity of kissing as a custom, some researchers argue. Herpesviruses, in general, have been around since long before the Bronze Age. But around that time, mass migrations of people from Eurasia to Europe — and the make-out sessions that took place along the way — may have helped fuel the rise of the modern version of HSV-1. 

3. Viruses named for Norse gods 

Scientists uncovered the genetic traces of a mysterious group of viruses that can infect Asgard archaea , ancient microbes that existed on Earth prior to the first complex cells . These viruses, named after figures in Norse mythology, may have influenced the rise of complex life on Earth, in part, by supplying a precursor to the nucleus that now carries DNA in complex cells. 

4. 'Mono' virus might trigger autoimmune disease 

The virus behind "mono" may fuel the development of multiple sclerosis (MS), an autoimmune disease that affects the brain and spinal cord, in people susceptible to the disease. Scientists are still learning why the virus, called Epstein-Barr virus, is strongly linked to MS, but they have a few theories as to how it might trigger the disease. 

5. Giant viruses in Arctic lake 

The Milne Fiord epishelf lake lies fewer than 500 miles (800 kilometers) from the North Pole and contains giant viruses that infect its resident algae. Such giant viruses can measure larger than some bacteria and contain comparably complex DNA. Scientists are still discovering new varieties of giant viruses, learning how their genes work and how they infect cells. 

6. Viruses slay superbugs 

Viruses that infect bacteria, or "bacteriophages," can make antibiotics more effective , clearing away drug-resistant superbugs that would otherwise defy treatment. In one fascinating case, doctors cultured viruses in lab dishes alongside a bacterial superbug and then selected the best killer from the bunch. They then unleashed that selected virus into a woman's chronic infection, helping to finally cure it. 

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7. Ancient viruses show widespread activity in human body 

Remnants of ancient viruses can be found scattered throughout the human genome. Once considered non-functional "junk DNA," it turns out that these genetic snippets are actually active in tissues throughout the body . What these viruses do in healthy tissue is still a mystery, and the answer is likely different in each tissue type. 

8. Never-before-seen viruses found in the ocean 

A team of scientists scoured the world's oceans for viruses containing RNA, a molecular cousin of DNA. Overall, they identified about 5,500 never-before-seen RNA virus species during their quest. To categorize all the new viruses, the team proposed doubling the number of taxonomic groups used to classify RNA viruses, from the existing five phyla to 10 phyla. 

9. Ocean viruses may affect flow of carbon through the ecosystem 

Thousands of RNA viruses recently discovered in the world's oceans infect a wide variety of hosts , including fungi, algae, amoebas and even some invertebrates. By infecting organisms that pull carbon dioxide out of the atmosphere, these mysterious viruses may influence how carbon flows through the ocean at large, scientists say. 

10. Virus-carrying ticks break record 

A shockingly high number of ticks at the Lawrence Township Recreational Park in Pennsylvania carry a potentially life-threatening virus called deer-tick virus, which can be transmitted to humans through tick bites. Of 25 ticks sampled from the park in a recent survey, 92% tested positive for the virus. By comparison, the highest infection rate among ticks previously measured at a single U.S. site was 25%. 

11. Climate change may push 'Japanese encephalitis' outbreaks south 

"Japanese encephalitis " (JE), a viral disease that can sometimes spark dangerous inflammation in the brain, reached southern Australia in 2022, a region where it hadn't previously spread. The JE virus gets passed to humans through the bites of infected mosquitoes and typically affects people in Asia and parts of the Western Pacific. Its appearance in Victoria, New South Wales, South Australia and Queensland hints that climate change may be expanding the disease's range southward.

12. Was the famous 'Russian flu' a coronavirus? 

A mysterious illness that emerged in Russia in the late 1880s and then spread around the globe may have been caused by a coronavirus , some scientists think. Known as the "Russian flu ," the virus caused a pandemic eerily similar to the ongoing COVID-19 pandemic , but researchers are still hunting for hard evidence of the virus' true identity. If they can find this evidence, they plan to investigate whether a descendent of the virus is still circulating today, perhaps causing milder disease than its predecessor. 

Nicoletta Lanese is the health channel editor at Live Science and was previously a news editor and staff writer at the site. She holds a graduate certificate in science communication from UC Santa Cruz and degrees in neuroscience and dance from the University of Florida. Her work has appeared in The Scientist, Science News, the Mercury News, Mongabay and Stanford Medicine Magazine, among other outlets. Based in NYC, she also remains heavily involved in dance and performs in local choreographers' work.

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I study viruses: How our team isolated the new coronavirus to fight the global pandemic

Professor of Pathology and Molecular Medicine and Acting Vice President, Research, McMaster University

Disclosure statement

Karen Mossman receives funding from the Natural Sciences and Engineering Council of Canada and the Canadian Institutes for Health Research.

McMaster University provides funding as a founding partner of The Conversation CA.

McMaster University provides funding as a member of The Conversation CA-FR.

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As most people rush to distance themselves from COVID-19, Canadian researchers have been waiting eagerly to get our (gloved) hands on the hated virus.

We want to learn everything we can about how it works, how it changes and how it interacts with the human immune system, so we can test drugs that may treat it, develop vaccines and diagnostics and prevent future pandemics.

This is what researchers live to do. Much of our everyday work is incremental. It’s important and it moves the field forward, but to have a chance to contribute to fighting a pandemic is especially inspiring and exciting.

The secret lives of viruses

Viruses are fascinating. They are inert microscopic entities that can either hide out, innocuous and undetected, or wreak pandemic havoc.

They are simultaneously complex and simplistic, which is what makes them so interesting — especially new, emerging viruses with unique characteristics. Researching viruses teaches us not only about the viruses we study, but also about our own immune systems.

Read more: Coronavirus weekly: expert analysis from The Conversation global network

The emergence of a new coronavirus in a market in Wuhan, China, in December 2019 set in motion the pandemic we are now witnessing in 160 countries around the world. In just three months, the virus has infected more than 360,000 people and killed more than 16,000 .

Viral isolation

The outbreak sent researchers around the world racing to isolate laboratory specimens of the virus that causes COVID-19. The virus was later named severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2.

In countries that experienced earlier outbreaks, including China, Australia, Germany and the United States, researchers were able to isolate the virus and develop their own inventories of SARS-CoV-2, but logistical and legal barriers prevented them from readily sharing their materials with researchers beyond their borders.

What Canadian researchers needed to join the fight in earnest was a domestic supply of clean copies of the virus — preferably from multiple Canadian COVID-19 cases. Even in a pandemic, developing such a supply is not as easy as it might sound, and multiple teams in Canada set out to isolate and develop pure cultures of the virus, not knowing which would be successful, or when.

Ultimately two teams in Canada would isolate the virus for study: one at the University of Saskatchewan and one that featured researchers from McMaster University, Sunnybrook Health Sciences Centre and the University of Toronto .

Arinjay Banerjee, a postdoctoral research fellow at McMaster who typically works in my virology lab , volunteered his special expertise. We were proud to have him share his talent with the team in Toronto, where he set to work with physicians and researchers Samira Mubareka, Lily Yip, Patryk Aftanas and Rob Kozak.

For Banerjee, it was like a batter being called to the plate with the score tied in the bottom of the ninth. He had come to work at McMaster because of its Institute for Infectious Disease Research and its Immunology Research Centre , and because the university maintains a research colony of bats .

Banerjee’s PhD work at the University of Saskatchewan, and now at McMaster, has focused on bats and how their viruses, including coronaviruses, interact with bat and human antiviral responses . Over the past few years, studies have shown that bat coronaviruses have the capacity to infect human cells. Multiple researchers had predicted a coronavirus that would evolve and jump into humans .

Read more: It's wrong to blame bats for the coronavirus epidemic

Ideal viral conditions

Isolating a virus requires collecting specimens from patients and culturing, or growing, any viruses that occur in the samples. These viruses are obligate intracellular parasites, which means that they can only replicate and multiply in cells. To isolate a particular virus, researchers need to provide it with an opportunity to infect live mammalian cells, in tiny flasks or on tissue culture plates.

Viruses adapt to their hosts and evolve to survive and replicate efficiently within their particular environment. When a new virus such as SARS-CoV-2 emerges, it isn’t obvious what particular environment that virus has adapted to, so it can be hard to grow it successfully in the lab.

We can use tricks to draw out a virus. Sometimes the tricks work and sometimes they don’t. In this case, the researchers tried a method Banerjee and the team had previously used while working on the coronavirus that causes Middle Eastern Respiratory Syndrome : culturing the virus on immunodeficient cells that would allow the virus to multiply unchecked. It worked.

Since specimens from patients are also likely to contain other viruses, it is critical to determine if a virus growing in the culture is really the target coronavirus. Researchers confirm the source of infection by extracting genetic material from the virus in culture and sequencing its genome.

They compare the sequence to known coronavirus sequences to identify it precisely. Once a culture is confirmed, researchers can make copies to share with colleagues.

All this work must be done in secure, high-containment laboratories that mitigate the risk of accidental virus release into the environment and also protect scientists from accidental exposure. The more versions of a virus that can be isolated, the better. Having multiple virus isolates allows us to monitor how the virus is evolving in humans as the pandemic progresses. It also allows researchers to test the efficacy of vaccines and drugs against multiple mutations of the virus.

Canadian viral strains

Both the Saskatchewan and Ontario teams are now able to make and share research samples with other Canadian scientists , enabling important work to proceed, using a robust domestic supply that reflects the evolving virus in its most relevant mutations.

That in turn gives Canadian researchers a fighting chance to deliver a meaningful blow to COVID-19 while there is still time. I’m glad our colleagues at other Canadian institutions will also have versions of the virus to use in their research.

There is still so much work for all of us to do.

• Coronavirus
• Middle East Respiratory Syndrome (MERS)

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RNA Viruses: A Case Study of the Biology of Emerging Infectious Diseases

Affiliation.

• 1 Centre for Immunity, Infection & Evolution, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom.
• PMID: 26184815
• PMCID: PMC6157708
• DOI: 10.1128/microbiolspec.OH-0001-2012

There are 180 currently recognized species of RNA virus that can infect humans, and on average, 2 new species are added every year. RNA viruses are routinely exchanged between humans and other hosts (particularly other mammals and sometimes birds) over both epidemiological and evolutionary time: 89% of human-infective species are considered zoonotic and many of the remainder have zoonotic origins. Some viruses that have crossed the species barrier into humans have persisted and become human-adapted viruses, as exemplified by the emergence of HIV-1. Most, however, have remained as zoonoses, and a substantial number have apparently disappeared again. We still know relatively little about what determines whether a virus is able to infect, transmit from, and cause disease in humans, but there is evidence that factors such as host range, cell receptor usage, tissue tropisms, and transmission route all play a role. Although systematic surveillance for potential new human viruses in nonhuman hosts would be enormously challenging, we can reasonably aspire to much better knowledge of the diversity of mammalian and avian RNA viruses than exists at present.

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The Coronavirus Crisis

For scientists who study virus transmission, 2020 was a watershed year.

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Researches have learned a lot in 2020 about how the coronavirus spreads through the air. Francesco Carta fotografo/Getty Images hide caption

Researches have learned a lot in 2020 about how the coronavirus spreads through the air.

When Linsey Marr looks back at the beginning of 2020, what strikes her is how few people in the world really understood how viruses can travel through the air.

"In the past year, we've come farther in understanding airborne transmission, or at least kind of beyond just the few experts who study it, than we have in decades," says Marr. "Frankly, I thought it would take us another 30 years to get to where we are now."

The urgency of the coronavirus pandemic thrust her once obscure field into the spotlight, as everyone from public health experts to ordinary citizens tried to gauge the safety of myriad activities, such as going to the grocery store, swimming at the beach or gathering for a party.

"Back in January, the understanding of how viruses spread through the air was really primitive and incorrect," says Marr , a researcher at Virginia Tech who has spent years studying virus transmission. "It's been pretty wild to see airborne transmission of viruses become big news."

Why These Tiny Particles Are A Big Deal

At the start of this coronavirus outbreak, the prevailing assumption among many medical experts was that respiratory viruses primarily spread through droplets of saliva and mucus that fly into the air after a cough or a sneeze. These were thought to travel only a short distance before falling to a surface. Public health messages consequently urged people to wash their hands and avoid touching their faces.

The coronavirus wasn't thought to be " airborne ," a word associated with viruses like the one that causes measles. An airborne virus was widely considered to be a germ that could travel in tiny particles called aerosols that hang suspended in the air and linger for quite a while, potentially traveling long distances.

Goats and Soda

Coronavirus faqs: why can't the cdc make up its mind about airborne transmission.

But, in reality, there's no clear cutoff between a virus that travels in aerosols and one that travels in larger droplets, says Marr. Infected people can give off respiratory viruses in particles of all different sizes that can travel a variety of distances, and big droplets can evaporate away into smaller ones. Very close to an infected person, the concentration of airborne virus could be high, and others could simply inhale it.

As the new coronavirus began to spread, it sure seemed like airborne spread — at short range — might be critical.

"Once it became more apparent that this was a really important route of transmission, you know, I and others started making noise about this," says Marr, who sent out a tweet in early March that said, "Let's talk about #airborne transmission of #SARSCOV2 and other viruses. A discussion is needed to improve accuracy and reduce fear associated with the term."

Let's talk about #airborne transmission of #SARSCOV2 and other viruses. A discussion is needed to improve accuracy and reduce fear associated with the term. /1 — Linsey Marr https://www.threads.net/@linseycmarr (@linseymarr) March 5, 2020

Meanwhile, scientific research on how the coronavirus moved through the air was being conducted at an astonishingly rapid pace.

"We're not even 12 months in, and we know things about this virus that we don't know about viruses that have been around for decades," says Josh Santarpia , a researcher at the University of Nebraska Medical Center.

He notes that no one has been able to grow measles virus from an air sample and yet some people insisted that this kind of proof was needed before saying that the novel coronavirus could be airborne.

"It was interesting that the burden of proof was so high for this virus when it wasn't for these other things that we just sort of generally consider to be airborne," says Santarpia.

His medical center took care of some of the first people with the coronavirus in the United States, and Santarpia recalls standing at the end of their beds with a device that collected air while they talked or breathed. His lab then analyzed the tiny airborne droplets, looking for the genetic signature of the coronavirus.

VIDEO: How To Protect Yourself From Coronavirus That Can Linger In The Air

"We were getting positives, more than one positive in the air samples," says Santarpia. "I was shocked." Signs of the virus were in such tiny particles that he worried that nothing less than the most protective masks could stop it.

Soon, though, studies showed that even simple masks are able to reduce the amount of virus that gets out into the air, cutting the risk of transmission. Suddenly mask-wearing became an ordinary — if politically contentious — part of everyday life.

Santarpia was floored at how quickly ventilation became a normal subject of conversation for the public.

"You know, 'How well ventilated is this space? Should I be spending time inside or outside?' " says Santarpia. "It's changed so much about the way we view the world."

Whether this will be a lasting change is an open question.

Donald Milton , a researcher at the University of Maryland, has spent a quarter-century thinking about the transmission of respiratory viruses through the air and has published studies showing that better ventilation in offices and dormitories is associated with a lower risk of virus transmission.

He's hoping the experience of this past year will lead to better engineering solutions being put in place to improve the overall safety of houses and other indoor spaces — things like enhanced ventilation, air filters or special lights up by a room's ceiling to disinfect the circulating air.

"How can we make indoor spaces safe so that we can keep our economy running and fight a pandemic without all the damage that we are seeing from the interventions that we have been forced to take this year?" says Milton. "I want to see us understand how it is that you can make a restaurant a safe place to be during a flu season and during a pandemic."

He thinks it's doable, but he worries that once vaccines get the coronavirus in check, people will just lose interest — until the next time there's a new virus that can be transmitted through the air.

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• coronavirus spread
• airborne transmission

11 real and famous cases of malware attacks

• Updated at June 4, 2021
• Blog , Threat Research

Many cases of famous hacker attacks use malware at some point. For example, first, the cybercriminal can send you a phishing email . No attachment. No links. Text only. After he gains your trust , in a second moment, he can send you a malicious attachment , that is, malware disguised as a legitimate file.

Malware  is a malicious software designed to infect computers and other devices. The intent behind the infection varies. Why? Because the cybercriminal can use malware to make money, to steal secret information that can give strategic advantages, to prevent a business from running or even just to have fun.

Yes, there are hackers who act for pleasure.

In fact, malware is a broad term. It’s like a category. Within this category are different types of threats, such as  virus ,  worm ,  trojan , and  ransomware .

To fight malware delivered via email, here at Gatefy we offer a  secure email gateway solution  and an  anti-fraud solution based on DMARC . You can request a demo or more information .

To get an idea, according to the FBI , damages caused by ransomware amounted to more than USD 29.1 million just in 2020. And one of the most widely used form of malware spreading continues to be via email . As a Verizon report confirmed : 30% of the malware was directly installed by the actor, 23% was sent there by email and 20% was dropped from a web application.

The cases listed below show how malware attacks can work and give you a glimpse of the harm they cause to businesses and individuals.

In this post, we’ll cover the following malware cases:

Table of Contents

Check out 11 real cases of malware attacks

1. covidlock, ransomware, 2020.

Fear in relation to the Coronavirus (COVID-19) has been widely exploited by cybercriminals. CovidLock ransomware is an example. This type of ransomware infects victims via malicious files promising to offer more information about the disease.

The problem is that, once installed, CovidLock encrypts data from Android devices and denies data access to victims. To be granted access, you must pay a ransom of USD 100 per device.

2. LockerGoga, ransomware, 2019

LockerGoga is a ransomware that hit the news in 2019 for infecting large corporations in the world, such as Altran Technologies and Hydro. It’s estimated that it caused millions of dollars in damage in advanced and targeted attacks.

LockerGoga infections involve malicious emails , phishing scams and also credentials theft. LockerGoga is considered a very dangerous threat because it completely blocks victims’ access to the system.

3. Emotet, trojan, 2018

Emotet is a trojan that became famous in 2018 after the U.S. Department of Homeland Security defined it as one of the most dangerous and destructive malware. The reason for so much attention is that Emotet is widely used in cases of financial information theft, such as bank logins and cryptocurrencies.

The main vectors for Emotet’s spread are malicious emails in the form of spam and phishing campaigns . 2 striking examples are the case of the Chilean bank Consorcio, with damages of USD 2 million, and the case of the city of Allentown, Pennsylvania, with losses of USD 1 million.

4. WannaCry, ransomware, 2017

One of the worst ransomware attacks in history goes by the name of WannaCry , introduced via phishing emails in 2017. The threat exploits a vulnerability in Windows.

It’s estimated that more than 200,000 people have been reached worldwide by WannaCry, including hospitals, universities and large companies, such as FedEx, Telefonica, Nissan and Renault. The losses caused by WannaCry exceed USD 4 billion.

By the way, have you seen our article about the 7 real and famous cases of ransomware attacks ?

5. Petya, ransomware, 2016

Unlike most ransomware , Petya acts by blocking the machine’s entire operating system. We mean, Windows system. To release it, the victim has to pay a ransom.

It’s estimated that the losses involving Petya and its more new and destructive variations amount to USD 10 billion since it was released in 2016. Among the victims are banks, airports and oil and shipping companies from different parts of the world.

6. CryptoLocker, ransomware, 2013

The CryptoLocker is one of the most famous ransomware in history because, when it was released in 2013, it used a very large encryption key, which made the experts’ work difficult. It’s believed that it has caused more than USD 3 million in damage, infecting more than 200,000 Windows systems.

This type of ransomware was mainly distributed via emails, through malicious files that looked like PDF files , but, obviously, weren’t.

7. Stuxnet, worm, 2010

The Stuxnet deserves special mention on this list for being used in a political attack, in 2010, on Iran’s nuclear program and for exploiting numerous Windows  zero-day vulnerabilities . This super-sophisticated worm has the ability to infect devices via USB drives, so there is no need for an internet connection.

Once installed, the malware is responsible for taking control of the system. It’s believed that it has been developed at the behest of some government. Read: USA and Israel.

8. Zeus, trojan, 2007

Zeus is a trojan distributed through malicious files hidden in emails and fake websites, in cases involving phishing . It’s well known for propagating quickly and for copying keystrokes, which led it to be widely used in cases of credential and passwords theft, such as email accounts and bank accounts.

The Zeus attacks hit major companies such as Amazon, Bank of America and Cisco. The damage caused by Zeus and its variations is estimated at more than USD 100 million since it was created in 2007.

9. MyDoom, worm, 2004

In 2004, the MyDoom worm became known and famous for trying to hit major technology companies, such as Google and Microsoft. It used to be spread by email using attention-grabbing subjects, such as “Error”, “Test” and “Mail Delivery System”.

MyDoom was used for  DDoS  attacks and as a backdoor to allow remote control. The losses are estimated, according to reports, in millions of dollars.

10. ILOVEYOU, worm, 2000

The ILOVEYOU worm was used to disguise itself as a love letter, received via email. Reports say that it infected more than 45 million people in the 2000s, causing more than USD 15 billion in damages.

ILOVEYOU is also considered as one of the first cases of social engineering used in malware attacks. Once executed, it had the ability to self-replicate using the victim’s email.

Also see 10 real and famous cases of social engineering .

11. Melissa, virus, 1999

The Melissa virus infected thousands of computers worldwide by the end of 1999. The threat was spread by email, using a malicious Word attachment and a catchy subject: “Important Message from (someone’s name)”.

Melissa is considered one of the earliest cases of social engineering in history. The virus had the ability to spread automatically via email. Reports from that time say that it infected many companies and people, causing losses estimated at USD 80 million.

How to fight malware attacks

There are 2 important points or fronts to fight and prevent infections caused by malware.

1. Cybersecurity awareness

The first point is the issue regarding cybersecurity awareness. You need to be aware on the internet. That means: watch out for suspicious websites and emails . And that old tip continues: if you’re not sure what you’re doing, don’t click on the links and don’t open attachments.

2. Technology to fight malware

The second point involves the use of technology . It’s important that you have an anti-malware solution on your computer or device. For end-users, there are several free and good options on the market.

For companies, in addition to this type of solution, we always recommend strengthening the protection of your email network. As already explained, email is the main malware vector. So, an email security solution can rid your business of major headaches.

Here at Gatefy we offer an email gateway solution and a DMARC solution . By the way, you can request a  demo by clicking here  or ask for  more information . Our team of cybersecurity experts will contact you shortly to help.

Latest news

10 real and famous cases of bec (business email compromise), 8 reasons to use dmarc in your business, what is mail server.

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• 17 April 2024

Deadly diseases and inflatable suits: how I found my niche in virology research

• Nikki Forrester 0

Nikki Forrester is a science journalist based in Davis, West Virginia.

You can also search for this author in PubMed   Google Scholar

You have full access to this article via your institution.

Hulda Jónsdóttir wears inflatable protective suits like these to study lethal viruses. Credit: Spiez Laboratory

Virologist Hulda Jónsdóttir studies some of the world’s most pathogenic viruses at the Spiez Laboratory in Spiez, Switzerland. For her, highly pathogenic viruses are more often a source of curiosity than of concern. Jónsdóttir, who runs a research group at the Spiez Laboratory, regularly dons a giant, inflatable protective suit to research disinfectants and antiviral compounds to combat several lethal viruses, including Ebola virus and Lassa virus. Jónsdóttir spoke to Nature about carving her own path in virology research and why she chose to pursue a career in Switzerland and at the Spiez Laboratory, which is owned and funded by the Swiss government.

Why do you study lethal viruses?

I’ve always been fascinated by viruses. They comprise barely anything, yet they have such a big impact on living organisms. Most of the viruses my lab and I study are highly pathogenic and lethal, such as Ebola virus, Lassa virus, Nairovirus and Nipah virus. Because these are all so lethal and don’t have vaccines or cures, they’re considered biosafety level (BSL) four. I have to wear a big inflated suit that’s attached to an air supply outside the room when I conduct my experiments.

What are you working on now?

My colleagues and I just started a three-year project to develop a model for testing antivirals against Nipah viruses, which are respiratory viruses that cause encephalitis. I also do disinfection studies for highly pathogenic viruses. Right now, we are looking at how effective homemade soap is as a disinfectant for Lassa virus, which is endemic in Nigeria as well as some other countries in West Africa.

What led you to your position at the Spiez Laboratory?

After I finished my PhD in virology at the Swiss Federal Institute of Technology (ETH) in Zurich in 2016, I stayed in the lab for a year as a postdoctoral researcher. By that point, I wasn’t sure whether I wanted to stay in science. Then I saw an advertisement for a two-year postdoctoral placement in respiratory toxicology at the University of Bern. I thought that the experience would help me determine whether I was tired of science as a whole or just feeling disillusioned with my current environment because I had been there for so long. There, I realized that I still liked doing science and that I missed virology research.

Two years later, I saw a postdoctoral job at the Spiez Laboratory to study an experimental Ebola vaccine. The project required BSL-4 work, which was something I had dreamt of doing since I started working in respiratory virology. I decided to apply for the position. It’s been five years, and I’m still here.

How does the Spiez Laboratory differ from academic labs?

We’re a government institution, and part of the Swiss Federal Office of Civil Protection. In the biology department, we have governmental mandates to do research that is relevant to Swiss civil protection, although of course we can focus on other topics as well. I do a lot of applied research that benefits the public, such as trying to find antiviral drugs against infectious diseases. We also collaborate with the military by training soldiers for biological civil protection twice a year. During the COVID-19 pandemic, soldiers helped personnel from the Spiez Lab to run diagnostic tests for COVID-19.

Nature Spotlight: Switzerland

Along with research, we run a regular diagnostic service for hospitals and doctors who send samples to us to be tested. Unlike an academic lab, you need security clearance to work here.

How did the COVID-19 pandemic affect your research?

I started working on coronaviruses during my PhD, so I had a lot of experience with them by the time the pandemic hit. I was doing my BSL-4 training at the Spiez Laboratory when I first heard about COVID-19. At the time, I felt frustrated because I was progressing in my career and then got pulled back into coronavirus research. But I had to figure out how to research SARS-CoV-2 or my lab would have been shut down. By the middle of 2020, I was constantly being contacted by researchers to do antiviral drug tests, and by the military to do serological tests of soldiers. My colleagues and I analysed soldiers’ responses to the virus and estimated the percentage of asymptomatic people. Doing COVID-19 research was very chaotic for a while; everybody wanted results immediately. But in a way, I was grateful that I could still go to work, even if it was crazy busy. As a foreigner, I was far away from my family, so it was difficult being so isolated.

Why did you decide to stay in Switzerland?

I grew up in Iceland and always wanted to study abroad. I came to Switzerland 12 years ago and was planning on staying only for my PhD. But I kept ending up in good places with good people where I felt supported and inspired.

As superficial as it sounds, it’s also about the money. Switzerland invests a decent amount of money in science, and I’ve been fortunate to be part of projects that are already funded or easy to get funding for.

But I don’t think people always talk about how hard it is to move to a new country. When I first arrived in St Gallen, Switzerland, in 2012, I felt isolated because I didn’t know the language and had a hard time making friends. In January 2014, I moved to Bern, which was much better because there were more people around and I liked the city. I also joined an English-speaking theatre group called the Caretakers. I met a lot of people, some of whom are now my best friends. One big issue when you go abroad to do science is that a lot of your peers leave after their contracts end, so your friends become scattered around the world. My theatre group has been more constant; it’s been a lifesaver for me.

Any advice for early-career scientists?

It’s important to rest sufficiently if you want to do good research. The system is geared towards you working as much as possible, but you just end up burning out. If there’s anything I can recommend, it’s having more holiday time. In Switzerland, I have five weeks of holidays, four of which are legally mandated. But I recognize that I’m immensely privileged to be able to take so much time off. It’s not always possible, depending on someone’s financial situation, lab environment or the country they live in.

Academic culture often puts so much pressure on PhD students and postdocs that it squeezes them until there’s nothing left, which is something I’m heavily against. As a group of researchers, I think we should work towards changing that culture, in part by lobbying for more time off. As an individual, even if you can’t travel or take large chunks of time away from the lab, you can still put some distance between yourself and your job. For instance, if you’re working from home on a Friday, close your computer at five and put it in a different room. Just having a little bit of space helps you to work better.

Nature 628 , S4 (2024)

doi: https://doi.org/10.1038/d41586-024-01098-1

This interview has been edited for length and clarity.

This article is part of Nature Spotlight: Switzerland , an editorially independent supplement. Advertisers have no influence over the content.

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Viral Infections and Nutrition: Influenza Virus as a Case Study

• First Online: 11 December 2020

Cite this chapter

• William David Green 6 ,
• Erik A. Karlsson 7 &
• Melinda A. Beck 6  

Part of the book series: Nutrition and Health ((NH))

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3 Citations

Each year, influenza virus infects 3–5 million people with over 500,000 global deaths due to influenza-related complications. Adequate nutrition is essential for both the innate and adaptive immune response to influenza infection as well as vaccination efforts to reduce disease burden. Nutritional conditions such as undernutrition, obesity, and micronutrient deficiencies increase risk for influenza infection in adults and children alike. Further, influenza infection is known to influence nutritional status in a complex and vicious cycle. This review will provide a brief overview of the complexity of viral replications and then focus specifically on influenza virus and what is known and unknown about the interaction of nutritional conditions on influenza infection and vaccination, with a special focus on micronutrient contributions. Healthy nutritional status is vital for protection and resolution of influenza infections as well as other viral infections, and further work is necessary to understand and develop the potential for beneficial nutritional interventions against viral infections.

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Abbreviations

Acquired immunodeficiency syndrome

Adjusted odds ratio

Body mass index

Covalently closed circular DNA

C-C chemokine receptor 5

C-X-C chemokine receptor 4

Direct-acting antiviral

Deoxyribonucleic acid

Double-stranded DNA

Glutathione peroxidase

Hemagglutinin 1 neuraminidase 1

Hemagglutinin

Hepatitis B virus

Hepatitis C virus

Human immunodeficiency virus

Human rhinovirus

Herpes simplex virus

Intercellular adhesion molecule 1

International Committee on Taxonomy of Viruses

Immunoglobulin

Latency-associated transcripts

Messenger RNA

Neuraminidase

Natural killer cells

Relaxed circle DNA

Ribonucleic acid

Reactive oxygen species

Single-stranded DNA

Single-stranded RNA

Transforming growth factor

Tumor necrosis factor

Ultraviolet B

Vitamin D receptor

Vitamin K antagonist

World Health Organization

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Green, W.D., Karlsson, E.A., Beck, M.A. (2021). Viral Infections and Nutrition: Influenza Virus as a Case Study. In: Humphries, D.L., Scott, M.E., Vermund, S.H. (eds) Nutrition and Infectious Diseases . Nutrition and Health. Humana, Cham. https://doi.org/10.1007/978-3-030-56913-6_5

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Teaching viruses and epidemiology online.

This playlist can be used to teach about the biology of viruses and epidemiology in an online setting. The topics covered include the structures and transmission mechanisms of viruses, zoonotic diseases, viral outbreaks, viral evolution during an outbreak, and epidemiology.

By completing the resources in this playlist, students will be able to:

• List the ways in which viruses can differ from each other.
• Identify different components and characteristics of viruses and their role in infection.
• Calculate the size of a virus relative to a human cell.
• Use information collected in case studies to distill complex, real-world data, and perform basic calculations to make decisions on the spread of an infectious disease.
• Analyze and interpret data from a scientific figure. 
• Explain the term “zoonotic disease” and discuss some of the global patterns in mammals that carry these diseases.
• Use appropriate scientific terms, including “reservoir” and “spillover,” in describing a disease outbreak.
• Analyze and interpret sequence data to explain how viruses evolve over time during an outbreak.

This playlist can be used in AP/IB Biology and undergraduate college courses. 

Virus Explorer

In this Click & Learn, students explore the diversity of viruses based on structure, genome type, host range, transmission mechanism, and vaccine availability.

To use this resource as part of this playlist, have students explore the Click & Learn and complete the associated worksheet. The extension activity at the end of the worksheet is optional; you may want to assign it if students don’t have a strong understanding of relative size.

Patterns of Zoonotic Disease

In this Data Point activity, students analyze a published scientific figure from a study on the global distribution of zoonotic pathogens and their host species.

To use this resource as part of this playlist, use the questions in the “Educator Materials” to guide a class discussion. The full scientific paper is also available from the “Materials” box of this resource’s webpage; it can be used to give the students an opportunity to practice reading primary literature.

Epidemiology of Nipah Virus

In this activity, students analyze evidence, perform calculations and make predictions based on real-world data about a viral outbreak. Part of the activity involves watching the related video Virus Hunter: Monitoring Nipah Virus in Bat Populations (resource 4 in this playlist).

To use this resource as part of this playlist, have students complete the “Student Handout,” watching the video when instructed.

You can supplement this activity by having students research the COVID-19 outbreak in Wuhan, China using this paper or in another region citing their references. They can write a mini-case study (using Part 1 of this activity as a template) to demonstrate the knowledge they’ve gained.

Virus Hunter: Monitoring Nipah Virus in Bat Populations

This video follows scientists working in Bangladesh as they test fruit bat populations to determine whether they are infected with Nipah virus, a potentially deadly human pathogen.

To use this resource as part of this playlist, refer to the notes accompanying the “Epidemiology of Nipah Virus” activity (resource 3 in this playlist).

Ebola: Disease Detectives

In this activity, students analyze DNA sequences of Ebola viruses to track the virus’s spread during the 2013–2016 Ebola outbreak in West Africa. Part of the activity involves watching the related video Think Like a Scientist: Natural Selection in an Outbreak (resource 6 in this playlist) .

To use this resource as part of this playlist:

• Have students complete up through Part 1 of the “Student Worksheet,” watching the video when instructed. It is recommended to provide this section of the worksheet separately, since Part 2 gives away some answers.
• The worksheet asks students to sort cards of DNA sequences. Students can do this online without printing cards by analyzing the “Sequence Sheet” PDF and writing down the sequence numbers for each grouping.
• After students finish Part 1, have them complete Part 2.

You can supplement this activity by having students compare and contrast methods used to track Ebola, Nipah, and the COVID-19 outbreak they may have researched in resource 3 of this playlist.

Think Like a Scientist: Natural Selection in an Outbreak

This video focuses on the front lines of the 2013–2016 Ebola outbreak in West Africa and explains how scientists monitored the evolution of the virus by analyzing its genome.

To use this resource as part of this playlist, refer to the notes accompanying the “Ebola: Disease Detectives” activity (resource 5 in this playlist).

Age Structure of Ebola Outbreaks

In this Data Point activity, students analyze a published scientific figure from a study that investigated demographic patterns in Ebola outbreaks from the Democratic Republic of the Congo.

To use this resource as part of this playlist, use the questions in the “Educator Materials” to guide a class discussion. The full scientific paper is also available under “Primary Literature” in the “Details” section from this resource’s webpage; it can be used to give the students an opportunity to practice reading primary literature.

You can supplement this activity by having students research demographic patterns in another outbreak, such as COVID-19 or Nipah. Based on their research, they can create a similar figure representing the age structure of the outbreak they chose.

Influenza: A case study

Introduction

Most people have suffered from influenza (flu) at some time in their lives, so you probably have personal experience or a good idea of the symptoms and progression of the disease. However, influenza is actually one of the world’s most serious diseases. The pandemic of flu that occurred in 1918, immediately following the First World War, is thought to have killed up to 50 million people: many more than died in the war itself. More recently, the 2009 ‘swine flu’ pandemic caused widespread panic across parts of the world, although it resulted in relatively few fatalities.

The following course is a case study of influenza that considers a range of topics such as the nature of the virus itself, its spread, treatment, and diagnosis. There are activities to complete and videos to watch as you work through the text, and a set of self-assessment questions at the end of the course that allow you to judge how well you have understood the course content.

This OpenLearn course is an adapted extract from the Open University course : SK320 Infectious disease and public health .

Learning outcomes

After studying this course, you should be able to:

define and use, or recognise definitions and applications of, each of the glossary terms in the course

describe influenza viruses, their structure, how they are transmitted, how they infect cells and replicate and how they produce their damage in the host

outline the different types of immune defence which are deployed against flu infections, distinguishing those that act against infected cells from those that act against free virus

describe how strains of the virus change over time, and relate this to the flu viruses that occur in birds and other mammals

explain how the epidemic pattern of influenza can be related to the evolution of new strains of virus and to the specificity of the immune response against each strain.

1 Background to the case study

Influenza is a myxovirus belonging to the family of viruses known as Orthomyxoviridae. The virus was originally confined to aquatic birds, but it made the transition to humans 6000–9000 years ago, coinciding with the rise of farming, animal husbandry and urbanisation.

These changes in human behavior and population density provided the ecological niche that enabled influenza, as well as a number of other infectious agents such as the viruses that cause measles and smallpox, to move from animals and adapt to a human host.

Influenza as a disease has been recognised for centuries, even though the viruses which cause it were not correctly identified until the early 1930s, first in the UK and then in the USA. Indeed the name itself is derived from an Italian word meaning ‘influence’, and reflected the widespread belief in medieval times that the disease was caused by an evil climatic influence due to an unfortunate alignment of the stars.

Our current understanding – that infectious diseases are caused by infectious agents – is so ingrained that such mystical causes for an illness now seem absurd. However, even during the Middle Ages, people had a sound idea of infection and realised that some diseases could be passed from one individual to another and others could not. For example, the use of quarantine for a disease such as plague, but not for many other illnesses, shows that people could distinguish infectious diseases from non-infectious diseases even if the causative agent and the method of transmission were obscure.

The idea that influenza is caused by the influence of the stars, though not a satisfactory explanation of how the disease spread, does identify an important feature of flu – that serious epidemics of the disease occur at irregular intervals.

For example, in the twentieth century there were at least five major epidemics of flu that spread around the world (a pandemic), and there were less serious epidemics in most years. In times when people believed in the spontaneous generation of life, the stars would have seemed a reasonable explanation for unpleasant and unexpected epidemics.

1.1 Defining influenza

How would you define ‘influenza’?

You may well have defined influenza as an infection caused by an influenza virus. However, you may have defined it according to its symptoms: an infection that starts in the upper respiratory tract, with coughing and sneezing, spreads to give aching joints and muscles, and produces a fever that makes you feel awful; but usually it has gone in 5–10 days and most people make a full recovery.

The first answer here is the biological definition and, in the Open University course SK320, diseases are defined according to the infectious agent which produces them. This is because different infections can produce the same symptoms, and the same infectious agent can produce quite different symptoms in different people, depending on their age, genetic make-up or the tissue of the body that becomes infected. Here a distinction is made between the infectious disease caused by a particular agent and the disease symptoms.

Unfortunately there is a lot of confusion in common parlance about different diseases. Often, people say that they have ‘a bit of flu’ when they have an infection with some other virus, or a bacterium that produces flu-like symptoms. Such loose terminology is understandable, since most people are firstly concerned with the symptoms of their disease. But to treat and control disease requires accurate identification of the causative agent, so this is the starting point for considering any infectious disease.

Attributing cause to a disease

The difficulties encountered in assigning a particular pathogen to a disease are well-illustrated by influenza.

During the influenza pandemic that occurred in 1890, the microbiologist Pfeiffer isolated a novel bacterium from the lungs of people who had died of flu. The bacterium was named Haemophilus influenzae and since it was the only bacterium that could be regularly cultivated from these individuals at autopsy, it was assumed that H. influenzae was the causative agent of flu.

Again, in the 1918 flu pandemic, the bacterium could be regularly cultivated from people who had died of flu with pneumonia. So it was thought that flu was caused by the bacterium, and H. influenzae came to be called the ‘influenza bacillus’.

The role of H. influenzae was only brought into question in the early 1930s, when Smith, Andrews and Laidlaw showed that it was possible to transfer a flu-like illness from the nasal washings of an infected person to ferrets, using a bacteria-free filtrate. These studies demonstrated that the pathogen was in fact much smaller than any known bacterium and paved the way to the identification of influenza viruses (Figure 1).

Electron micrograph picture of influenza viruses. Each viral particle is about 500 nm across and surrounded by a darker-staining lipid bilayer coat derived from the host cell.

Why do you suppose that H. influenzae was incorrectly identified as the causative agent of flu?

The bacterium fulfils two of Koch’s postulates: it is regularly found in serious flu infections and it can be cultured in pure form on artificial media. Moreover, at that time no-one knew what a virus was, and everyone was thinking in terms of bacterial causes for infectious diseases.

Although the precise role of H. influenzae in the 1890 and 1918 flu pandemics is not clear, it is likely that the bacteria were present and acting in concert with the flu virus to produce the pneumonia experienced. Such synergy between virus and bacteria was demonstrated by Shope in 1931. He infected pigs with a bacterial-free filtrate (containing swine influenza virus) with or without the bacteria, and showed that the disease produced by the bacteria and filtrate together was more severe than that produced by either one alone (Van Epps, 2006).

In its role of co-pathogen, H. influenzae is only one of a number of bacteria that can exacerbate the viral infection. This highlights a very important point. In the tidy world of a microbiology or immunology laboratory, scientists typically examine the effect of one infectious agent in producing disease. In the real world, people often become infected with more than one pathogen. Indeed, infection with one agent often lays a person open to infection with another, as immune defences become overwhelmed. For this reason, a particular disease as seen by physicians may be due to a combination of pathogens.

1.2 Influenza infection in humans

Influenza is an acute viral disease that affects the respiratory tract in humans. The virus is spread readily in aerosol droplets produced by coughing and sneezing, which are symptoms of the illness. Other symptoms include fatigue, muscle and joint pains and fever.

Following infection, the influenza virus replicates in the cells lining the host’s upper and lower respiratory tract. Virus production peaks 1–2 days later, and virus particles are shed in secretions over the following 3–4 days. During this period, the patient is infectious and the symptoms are typically at their most severe.

After one week, virus is no longer produced, although it is possible to detect viral antigens for up to 2 weeks. Immune responses are initiated immediately after the virus starts to replicate, and antibodies against the virus start to appear in the blood at 3–4 days post infection. These continue to increase over the following days and persist in the blood for many months.

In a typical flu infection, the virus is completely eliminated from the host’s system within 2 weeks. This is sterile immunity: the virus cannot be obtained from the patient after recovery from the disease. Figure 2 shows the typical time course of an acute flu infection.

In this figure, the horizontal axis is labelled days and is marked from zero, which is the time of infection, up to 10 days at one-day intervals. There are three horizontal bars, labelled virus, symptoms and antibodies, and the depth of each bar corresponds to the amount of virus or antibody or the severity of symptoms respectively. Antibody production is maximal by day 5 and the virus is reduced to a very low level by day 6. Symptoms of infection disappear by day 9.

For infants, older people, and those with other underlying diseases (e.g. of the heart or respiratory system) an infection with flu may prove fatal. However, the severity of a flu epidemic and the case fatality rate depend on the strain of flu involved and the level of immunity in the host population.

During a severe epidemic, there are typically thousands more deaths than would normally be expected for that time of year, and these can be attributed to the disease. Although older people are usually most at risk from fatal disease, this is not always so. In the 1918 flu pandemic there was a surprisingly high death rate in people aged 20–40 (Figure 3), and this was also the case for the 2009 ‘swine flu’ pandemic.

The figure is a line graph in which the horizontal axis is labelled age and is marked in years from zero to 80 at intervals of 20 years. The vertical axis is labelled death rate per 100 000 population and is marked from zero to 3000 at intervals of 500 units. The 1917 plots for both males and females are almost identical U-shaped curves, and show that death rates were in excess of 1500 in newborns, dropped to 200 by age 2 and were zero in 10-year-olds. Rates remained below 200 for those aged 40 or under, increased to 500 in 65-year-olds, and beyond this age, death rate increased very rapidly to reach levels of 3000 per 100 000 for 80-year-olds. The pattern in death rates in 1918 for the younger and older age groups was similar to that in 1917, although rates in newborns were much higher, at 2500. The minimum rate in 1918, again observed in 10-year-olds, was 200. Beyond this age, death rates rose sharply, to 1200 for 30-year-old males and 750 for 30-year-old females. Death rates in both groups fell rapidly, and for those aged 60 or more, were similar to the rates in the previous year.

Older people are often most severely affected during infectious disease outbreaks because they may have a less effective immune response than younger people, or a reduced capacity to repair and regenerate tissue damaged by the infection. However, there are circumstances where older people may be more resistant to infection than younger people because they may have already encountered the disease (in their youth) and could retain some immunity and so be less susceptible than younger people who have not encountered the disease before.

1.3 Influenza infection in other species

Influenza viruses infect a wide range of species, including pigs, horses, ducks, chickens and seals. In most of these other species the virus produces an acute infection.

For example, in most of the mammals the symptoms are very similar to those in humans: an acute infection of the respiratory tract, which is controlled by the immune response although fatal infections occur in some species. However, in wild ducks and other aquatic birds the virus primarily infects the gut and the birds do not appear to have any physical symptoms.

Despite this, ducks may remain infected for 2–4 weeks and during this time they shed virus in their faeces. Potentially this is a very important reservoir of infection; although flu viruses do not often cross the species barrier, the pool of viruses present in other species is an important genetic reservoir for the generation of new flu viruses that do infect humans.

This reservoir becomes particularly important in certain farming communities or in crowded conditions where animals (especially pigs and ducks) are continuously in close proximity with humans (Branswell, 2010). Although such conditions occur in many agricultural communities throughout the world, they are typically observed in South-East and East Asia thereby contributing to these geographical areas often being the source of radically new ‘hybrid’ strains of influenza that incorporate genes from different species-specific strains. (The genetics of influenza are discussed in Section 2.3.)

When strategies for controlling a disease are considered, awareness of the possible presence of an animal reservoir of infection is very important. For example, an immunisation programme against flu would substantially reduce the incidence of the current strain in humans but, because there is always a reservoir of these viruses in other animals, and these viruses are constantly mutating, another strain would inevitably emerge and be unaffected by immunisation. It is useful to distinguish diseases such as rabies, which primarily affect other vertebrates and occasionally infect humans (zoonoses), from diseases such as flu where different strains of the virus can affect several species including humans.

Identify a fundamental difference between the way that zoonoses (e.g. rabies) are transmitted, and the way in which flu is transmitted.

Flu can be transmitted from one human being to another, whereas most zoonoses, including rabies, are not transmitted between people.

2 Influenza viruses

Viruses have very diverse genomes. Whereas the genomes of bacteria, plants and animals are of double-stranded DNA, the genomes of viruses can be constituted from either DNA or RNA and may be double- or single-stranded molecules.

Usually, DNA is a double-stranded molecule with paired, complementary strands (dsDNA) and RNA is a single stranded molecule (ssRNA). However, some viruses have single-stranded DNA genomes (ssDNA) and some have double-stranded RNA genomes (dsRNA). The type of nucleic acid found in the genome depends on the group of viruses involved.

RNA encodes protein in all living things, and the sequence of bases in the RNA determines the sequence of amino acids in the protein. A strand of RNA which has the potential to encode protein is said to be ‘positive sense’ (+). If a strand of RNA is complementary to this, then it is ‘negative sense’ (–). Negative-sense RNA must first be copied to a complementary positive-sense strand of RNA before it can be translated into protein.

The description of the influenza genome as negative-sense ssRNA means that its RNA cannot be translated without copying first. This copying is performed by influenza’s viral RNA polymerase, a small amount of which is packaged with the virus, ready to begin copying the viral genome once it enters a host cell. Viral RNA polymerase consists of three subunits: PB1, PB2, and PA, encoded separately by the first three viral RNA strands.

Understanding the way in which different viruses replicate is important, since it allows the identification of particular points in their life-cycle that may be susceptible to treatment with antiviral drugs.

Classification

Viruses are classified into different families, groups and subgroups in much the same way as are species of animals or plants.

As you have already read, the influenza viruses are (–)ssRNA organisms (Baltimore group V) and belong to a family called the Orthomyxoviruses (see Box 1). They fall into three groups: influenza A, B and C.

Type A viruses are able to infect a wide variety of endothermic (warm-blooded) animals, including mammals and birds, and analysis of their viral genome indicates that all strains of influenza A originated from aquatic birds.

By contrast, types B and C are mostly confined to humans. At any one time, a number of different strains of virus may be circulating in the human population.

Box 1 Families, groups and strains of virus

Viruses were originally classified into different groups according to similarities in their structure, mode of replication and disease symptoms. For example, the Orthomyxoviruses include viruses that cause different types of influenza, while Paramyxoviruses include the viruses that cause measles and mumps.

Such large groupings are often called a family of viruses. The families can be subdivided into smaller groups, such as influenza A, B and C. Even within a single such group of viruses there can be an enormous level of genetic diversity, and this is the basis of the different strains. As an example, two HIV particles from the same individual may be 4% different in their genome; compare this with the 1% difference between the genomes of humans and chimpanzees, which are different species.

2.1 Structure of influenza

The structure of influenza A is shown schematically in Figure 4. The viral genomic RNA, which consists of eight separate strands (see Section 2.3), is enclosed by its associated nucleoproteins to make a ribonucleoprotein complex (RNP), and this is contained in the central core of the virus (the capsid).

The nucleoproteins are required for viral replication and packing of the genome into the new capsid, which is formed by M1-protein (or matrix protein). The M1-protein is the most abundant component of the virus, constituting about 40% of the viral mass; it is essential for the structural integrity of the virus and to control assembly of the virus.

In this cross-sectional diagram of the spherical virus, the convoluted ribonucleoprotein genome with its replication enzymes is inside the capsid which comprises M-protein subunits. The envelope surrounds the capsid and is studded with molecules of haemagglutinin and neuraminidase.

Orthomyxoviruses have a capsid surrounded by a phospholipid bilayer derived from the plasma membrane of the cell that produced the virus. This layer is shown in Figure 4 as the virus’s envelope.

Two proteins, haemagglutinin and neuraminidase, are found on the viral envelope. These proteins are encoded by the viral HA and NA genes (Section 2.3), respectively and are inserted into the plasma membrane of the infected cell before the newly-produced viruses bud off from the cell surface.

The haemagglutinin can bind to glycophorin, a type of polysaccharide that contains sialic acid residues, and which is present on the surface of a variety of host cells. The virus uses the haemagglutinin to attach to the host cells that it will infect. Antibodies and drugs against haemagglutinin are therefore particularly important in limiting the spread of the virus, since they prevent it from attaching to new host cells.

Neuraminidase is an enzyme that cleaves sialic acid residues from polysaccharides. It has a role in clearing a path to the surface of the target cell before infection, namely, digesting the components of mucus surrounding epithelial cells in the respiratory system. Similarly, neuraminidase also promotes release of the budding virus from the cell surface after infection.

The structures of influenza B and influenza C are broadly similar to that of Type A, although in influenza C the functions of the haemagglutinin and the neuraminidase are combined in a single molecule, haemagglutinin esterase. This molecule binds and cleaves a less common type of sialic acid. Influenza C does not normally cause clinical disease or epidemics, so the following discussion is confined to influenza A and B.

2.2 Designation of strains of influenza

A considerable number of genetically different strains of influenza A have been identified, and these are classified according to where they were first isolated and according to the type of haemagglutinin and neuraminidase they express. For example ‘A/Shandong/9/93(H3N2)’ is an influenza A virus isolated in the Shandong province of China in 1993 – the ninth isolate in that year – and it has haemagglutinin type 3 and neuraminidase type 2.

At the start of the twenty-first century, the major circulating influenza A strains are H1N1 (‘swine flu’) and H3N2. At least 16 major variants of haemagglutinin and 9 variants of neuraminidase have been recognised, but to date most of these have only been found in birds.

The designation for influenza B is similar, but omits the information on the surface molecules, for example: ‘B/Panama/45/90’.

As you will see later, accurate identification of different strains of flu is crucial if we are to control epidemics by vaccination programmes.

2.3 Genomic diversity of influenza

The genome of flu viruses consists of around 14 000 nucleotides of negative-sense single-stranded RNA. Compare this number to the approximately 3 billion nucleotides found in the human genome or the 150 billion nucleotides of the genome of the marbled lungfish (the largest genome known in vertebrates).

The genome of influenza viruses is segmented, into eight distinct fragments of RNA containing 11 genes and encoding approximately 14 proteins (see Table 1 below). This structure has significance for the spread of the virus and the severity of disease symptoms.

Cases of influenza generally arise in two main ways: by provoking seasonal annual outbreaks or epidemics and, less commonly, through global pandemics. As you will see shortly, both of these phenomena occur as consequences of the fact that the virus uses RNA as its genetic template and that this RNA genome is segmented into discrete strands.

Footnotes  

The influenza virus is a successful pathogen because it is constantly changing. How might having a segmented genome promote the evolution of new strains of influenza virus?

If a cell is infected with more than one strain of virus at the same time, then a new strain can be generated simply by mixing RNA strands from different viruses.

2.3.1 Creation of new viral strains

Part of the success of influenza as a pathogen is because segmented genome improves the virus’s potential to evolve into new strains through the combination of different RNA stands. This mixing of the genetic material from different viral strains to produce a new strain is termed genetic reassortment .

For instance, the virus that caused the 2009 H1N1 ‘swine flu’ pandemic comprises a quadruple reassortment of RNA strands from two swine virus, one avian virus, and one human influenza virus:

• the surface HA and NA proteins derive from two different swine influenzas (H1 from a North American swine influenza and N1 from a European swine influenza)
• the three components of the RNA polymerase derive from avian and human influenzas (PA and PB2 from the avian source, PB1 from the human 1993 H3N2 strain)
• the remaining internal proteins derive from the two swine influenzas (MacKenzie, 2009).

This does not necessarily mean that all four viruses infected the same animal at once. The new strain was likely the result of a reassortment of two swine influenza viruses, one from North America and one from Europe. The North American virus may itself have been the product of previous reassortments, containing a human PB1 gene since 1993 and an avian PA and PB2 genes since 2001. The presence of avian influenza RNA polymerase genes in this virus was especially worrying, since the avian polymerase is thought to be more efficient than human or swine versions, allowing the virus to replicate faster and thus making it more virulent. Similar avian RNA polymerase genes are what make H5N1 bird flu extremely virulent in mammals and what made the 1918 human pandemic virus so lethal in people.

This mixing of genes from two or more viruses (whether from the same host species or from different species) can cause major changes in the antigenic surface proteins of a virus, such that it is no longer recognised by the host’s immune system. This antigenic shift is described in more detail in Section 3 (specifically, Box 2).

In contrast to the major genetic changes caused by reassortment, influenza viruses also undergo constant, gradual, genetic changes due to errors made by their RNA polymerases.

2.4 Infection and replication

Influenza RNA polymerase lacks the ability to recognise and repair any errors that occur during genome duplication, resulting in mistakes in copying its viral RNA about once in every 10 000 nucleotides. Because the influenza genome only contains approximately 14 000 nucleotides, this means that, on average, each new virus produced differs by 1 or 2 nucleotides from its ‘parent’.

The slow accumulation of random genetic changes, especially in the antigenic surface proteins, explains why antibodies that were effective against the virus one year may be less effective against it in subsequent years. This gradual change in the nature of viral antigens is known as antigenic drift .

The replication cycle of influenza is illustrated in Figure 5.

Complicated diagram showing a series of events from the replication cycle of a flu virus, from the virus entering a cell, releasing its contents, replicating, and these new virus particles budding and exiting the infected cell. Anti-clockwise, from the top left corner: (1) virus attaches to cell and is endocytosed; (2) cellular lysosomes fuse with endocytosed virus and viral RNA, and proteins are released into cell; (3) viral RNA moves to nucleus of the infected cell and is transcribed into viral mRNA, which is exported into cytosol to make new viral proteins; (4) viral proteins and viral RNA self-combine to make new viral particles that bud off the cell and are released to infect more host cells.

Influenza is spread in aerosol droplets that contain virus particles (or by desiccated viral nuclei droplets), and infection may occur if these come into contact with the respiratory tract. Viral neuraminidase cleaves polysaccharides in the protective mucus coating the tract, which allows the virus to reach the surface of the respiratory epithelium.

The haemagglutinin now attaches to glycophorins (sialic-acid-containing glycoproteins) on the surface of the host cell, and the virus is taken up by endocytosis into a phagosome. Acidic lysosomes fuse with the phagosome to form a phagolysosome and the pH inside the phagolysosome falls. This promotes fusion of the viral envelope with the membrane of the phagolysosome, triggering uncoating of the viral capsid and release of viral RNA and nucleoproteins into the cytosol.

The viral genomic RNA then migrates to the nucleus where replication of the viral genome and transcription of viral mRNA occur. These processes require both host and viral enzymes. The viral negative-stranded RNA is replicated by the viral RNA-dependent RNA polymerase, into a positive-sense complementary RNA (cRNA), and these positive and negative RNA strands associate to form double-stranded RNA (dsRNA). The cRNA strand is subsequently replicated again to produce new viral genomic negative-stranded RNA. Some of the cRNA is also processed into mRNA for translation of viral proteins. The infection cycle is rapid and viral molecules can be detected inside the host cell within an hour of the initial infection.

The envelope glycoproteins (haemagglutinin and neuraminidase) are translated in the endoplasmic reticulum, processed and transported to the cell’s plasma membrane. The viral capsid is assembled within the nucleus of the infected cell. The capsid moves to the plasma membrane, where it buds off, taking a segment of membrane containing the haemagglutinin and neuraminidase, and this forms the new viral envelope.

Influenza virus budding from the surface of an infected cell is shown in Figure 6.

In this false-colour electron micrograph, the budding virus particles appear orange and their surrounding envelopes appear green. One of the buds has a short stalk which indicates that virus particle is about to pinch off from the host cell membrane. Each virus is about 100 nanometres in diameter.

From the description above, identify a process or element in the replication cycle which is characteristic of the virus, and which would not normally occur in a mammalian cell.

The replication of RNA on an RNA template with the production of double-stranded RNA would never normally occur in a mammalian cell. Double stranded RNA is therefore a signature of a viral infection. Significantly, cells have a way of detecting the presence of dsRNA, and this activates interferons: molecules involved in limiting viral replication.

2.5 Cellular pathology of influenza infection

Flu viruses can infect a number of different cell types from different species. This phenomenon is partly because the cellular glycoproteins which are recognised by viral haemagglutinin are widely distributed in the infectious agent.

What is the term for the property of viruses that allows them to only replicate in particular cell types?

This property is viral tropism. Hence we can say that flu viruses have a broad tropism.

A second reason why the virus can infect a variety of cell types is that the replication strategy of flu is relatively simple: ‘infect the cell, replicate as quickly as possible and then get out again’. This is the cytopathic effect of the virus. Cell death caused directly by the virus can be distinguished from cell death caused by the actions of the immune system as it eliminates infected cells.

The effects of cell death

Cell death impairs the function of an infected organ and often induces inflammation , a process that brings white cells (leukocytes) and molecules of the immune system to the site of infection. In the first instance, the leukocytes are involved in limiting the spread of infection; later they become involved in combating the infection, and in the final phase they clear cellular debris so that the tissue can repair or regenerate.

The symptoms of flu experienced by an infected person are partly due to the cytopathic effect of the virus, partly due to inflammation and partly a result of the innate immune response against the virus. The severity of the disease largely depends on the rate at which these processes occur.

• In most instances, the immune response develops sufficiently quickly to control the infection and patients recover.
• If viral replication and damage outstrip the development of the immune response then a fatal infection can occur.

In severe flu infections, the lungs may fill with fluid as the epithelium lining the alveoli (air sacs) is damaged by the virus. The fluid is ideal for the growth of bacteria, and this can lead to a bacterial pneumonia, in which the lungs become infected with one or more types of bacteria such as Haemophilus influenzae . Damage to cells lining blood vessels can cause local bleeding into the tissues, and this form of ‘fulminating disease’ was regularly seen in post-mortem lung tissues of people who died in the 1918 pandemic.

3 Patterns of disease

In humans, pigs and horses, flu viruses circulate through populations at regular intervals. The disease is endemic in tropical regions for all of these host groups (i.e. it is continually present in the community). In temperate latitudes, infections are usually seasonal or epidemic, with the greatest numbers occurring in the winter months (Figure 7). Epidemics also occur sporadically in sea mammals and poultry, and in these species high mortality is typical.

In this graph, the horizontal axis is marked in years from 1994 to 1997. The vertical axis is labelled number of isolates per week and is marked from zero to 900 at intervals of 100. The data show that there were three separate epidemics, which occurred over the three successive winters, and in increasing order of severity. The peak numbers of isolates were as follows: in 1994/5, there were 370; in 1995/6, there were 630; and in 1996/9, there were nearly 900.

In most years, flu in humans affects a minority of the population, the disease course is not very severe and the level of mortality is not great. In such years the influenza virus is slightly different from the previous year due to antigenic drift, which results in the accumulation of genetic mutations that cause the molecules present on the surface of the virus change progressively. In this scenario, the virus is not significantly different from the previous year so that the host’s immune system can more easily mount an effective response than it could to a completely new strain.

However, at irregular intervals the virus undergoes an antigenic shift. This process only occurs in influenza A viruses, typically every 10–30 years, and it is associated with severe pandemics, serious disease and high mortality (see Box 2).

In Section 2.3 you read that strains of influenza are differentiated and designated using a simple system of numbers and letters that depend on their surface antigens. More commonly, however, strains responsible for pandemics are often given a common name according to the area in the world from which they were thought to originate, or the species they mainly affected before becoming transferred to humans (see Table 2). Evidence suggests, however, that in the twentieth century the major flu pandemics all originated in China, with the exception of the 1918 pandemic, which first occurred in the USA.

Box 2 The rise of H5N1 – an example of antigenic shift

In 1997, a new strain of influenza A, H5N1, was identified in Hong Kong. The strain was rife in chickens and a few hundred people had become infected. Mortality in these individuals was very high, (6 of 18 died), and so there was serious concern that it marked the beginning of a new pandemic. The authorities in Hong Kong responded by a mass cull of poultry in the region and about 1.5 million chickens were slaughtered. H5N1 did not spread easily from person to person and no further cases were reported in people following the slaughter.

Whether the H5N1 outbreak was an isolated incident of a strain spreading from chicken to humans, or whether it was the start of a major pandemic which was nipped in the bud, cannot be known. Subsequent analysis showed that the high virulence of the new strain could partly be related to the new variant of haemagglutinin (H5), and partly to a more efficient viral polymerase. This outbreak clearly demonstrates the way in which bird influenza can act as a source of new viral strains, and shows that such new strains may be very dangerous to humans.

Since the discovery of the influenza virus in the 1930s it has been possible to isolate and accurately identify each of the epidemic strains, but, as earlier strains of virus have now died out, it has been necessary to infer their identity by examining the antibodies in the serum of affected people.

Antibodies and the ability of the immune system to respond to a strain of flu are much more persistent than the virus itself. It is thus possible to analyse antibodies to determine which types of haemagglutinin and neuraminidase they recognise long after the virus itself has gone. One can then deduce which type of influenza virus that person contracted earlier in their life (as explained in Section 5.2).

3.1 Tracking the emergence of new strains

Influenza is one of several diseases monitored by the WHO Global Alert and Response (GAR) network (WHO, 2011a), comprising 110 ‘sentinel’ laboratories in 82 countries. The organisation’s surveillance and monitoring of the disease then forms part of their Global Influenza Programme (GIP), and they use data gathered from participating countries to:

• provide countries, areas and territories with information about influenza transmission in other parts of the world to allow national policy makers to better prepare for upcoming seasons
• provide data for decision making regarding recommendations for vaccination and treatment
• describe critical features of influenza epidemiology including risk groups, transmission characteristics, and impact
• monitor global trends in influenza transmission
• inform the selection of influenza strains for vaccine production (WHO, 2011b).

The influenza data from the sentinel laboratories is fed into a global surveillance programme, started by the WHO in 1996, called FluNet (WHO, 2011c), which is one of the tools that facilitates the actions described above.

Activity 1 Using FluNet

Use the link below to visit the WHO’s FluNet web page and locate and view the chart showing the global circulation of flu (in the section marked ‘View charts’) to find out which flu subtypes are currently the major ones in circulation in the human population.

Link to WHO FluNet web page

At the time of writing (2011), Influenza A (H5N1) and influenza B (unknown lineage) are the two main types globally. FluNet also breaks this information down into geographic areas and countries so, if you wish, you can see what subtypes are circulating where you live.

Typically a flu vaccine contains material from the main influenza A strains and an influenza B strain, so that an immune response is induced against the most likely infections. Usually the scientists predict correctly and immunised people are effectively protected against the current strains (>90% protection). However, the prediction is occasionally incorrect, or a new strain develops during the time that the vaccine is being manufactured. In this case the vaccine generally provides poor protection.

What can you deduce about immunity against flu infection from the observations on vaccination above?

The immune response is strain-specific. If you are immunised against the wrong strain of flu, then the response is much less effective and you are more likely to contract the disease.

3.2 Immune responses to influenza

The immune system uses different types of immune defence against different types of pathogen. The responses against flu are typical of those which are mounted against an acute viral infection, but different from the responses against infection by bacteria, worms, fungi or protist parasites.

When confronted with an acute viral infection, the immune system has two major challenges:

• The virus replicates very rapidly, killing the cells it infects. Since a specific immune response takes several days to develop, the body must limit the spread of the virus until the immune defences can come into play.
• Viruses replicate inside cells of the body, but they spread throughout the host in the blood and tissue fluids. Therefore, the immune defences must recognise infected cells (intracellular virus) and destroy them. But the immune system must also recognise and eradicate free virus in the tissue fluids (extracellular virus) in order to prevent the virus from infecting new cells.

The kinds of immune defence that the body deploys against flu are briefly considered in the next section.

3.2.1 Summary of the response

How does the body act quickly to limit viral spread?

When a virus infects a cell of the body, the molecular machinery for protein synthesis within the cell is usurped as the virus starts to produce its own nucleic acids and proteins. The cell detects the flu dsRNA and other viral molecules and releases interferons, which bind to receptors on neighbouring cells and cause them to synthesise antiviral proteins. If a virus infects such cells they resist viral replication, so fewer viruses are produced and viral spread is delayed.

Also, in the earliest stages of a virus infection the molecules on the cell surface change. Cells lose molecules that identify them as normal ‘self’ cells. At the same time they acquire new molecules encoded by the virus. A group of large, granular lymphocytes recognise these changes and are able to kill the infected cell. This function is called ‘natural killer’ cell action and the lymphocytes that carry it out are termed NK cells.

Non-adaptive and adaptive responses

The actions of both interferons and NK cells in combating infection by influenza occur early in an immune response, and are not specific for the flu virus. These defences occur in response to many different kinds of viral infection, and they are part of our natural, or non-adaptive, immune responses.

Note that immunologists use the term non-adaptive to indicate a type of response that does not improve or adapt with each subsequent infection. This is quite different to its use in evolutionary biology, where it means ‘not advantageous’. Such non-adaptive immune responses slow the spread of an infection so that specific, or adaptive, immune defences can come into play.

The key features of an adaptive immune response are specificity and memory. The immune response is specific to a particular pathogen, and the immune system appears to ‘remember’ the infection, so that if it occurs again the immune response is much more powerful and rapid. Because an immune response is highly specific to a particular pathogen it often means that a response against one strain of virus is ineffective against another – if a virus mutates then the lymphocytes that mediate adaptive immunity are unable to recognise the new strain.

There are two principal arms of the adaptive immune system, mediated by different populations of lymphocytes. One group, called T-lymphocytes, or T cells (which develop in the thymus gland, overlying the heart), recognises antigen fragments associated with cells of the body, including cells which have become infected. A set of cytotoxic T cells (Tc) specifically recognises cells which have become infected and will go on to kill them. In this sense they act in a similar way to NK cells. However they differ from NK cells in that Tc cells are specific for one antigen or infectious agent, whereas NK cells are non-specific.

The second group of lymphocytes are B cells (that differentiate in the bone marrow), which synthesise antibodies that recognise intact antigens, either in body fluids or on the surface of other cells. Activated B cells progress to produce a secreted form of their own surface antibody. Antibodies that recognise the free virus act to target it for uptake and destruction by phagocytic cells.

Therefore the T cells and NK cells deal with the intracellular phase of the viral infection, while the B cells and antibodies recognise and deal with the extracellular virus.

The two reactions described above are illustrated in Figure 8.

The first part of the diagram shows an antibody molecule binding to the virus and preventing it from entering the cell. The next part shows a virus entering and multiplying within a cell, causing the cell to release interferon. When the interferon reaches a neighbouring uninfected cell, it makes that cell resistant to infection. Also shown are a natural killer cell and a cytotoxic T cell. Either of these can bind to an infected cell via specific receptors on the cell surface, and kill that cell.

You might ask why it takes the adaptive immune response so long to get going. The answer is that the number of T cells and B cells that recognise any specific pathogen is relatively small, so first the lymphocytes which specifically recognise the virus must divide so that there are sufficient to mount an effective immune response. This mechanism is fundamental to all adaptive immune responses.

Activity 2 Influenza mini-lecture

Some of the themes that we have discussed up to now are presented in Video 1: a mini-lecture on influenza by David Male of The Open University. Watch the videos and then attempt the questions below

Transcript: Video 1 Influenza mini-lecture.

Influenza is a viral disease which generally starts with an infection of the upper respiratory tract and develops with systemic symptoms including fever and lassitude over the course of 1–2 weeks. Although it is debilitating, most people make a full recovery. However it may be fatal for older people and those with weaker immune systems, particularly if the virus disposes them to concurrent bacterial infections such as pneumonia.

The disease is caused by a group of myxoviruses, influenza A, B and C, although the most serious infections are caused by influenza A, and the following discussion refers to influenza A. The virus is seen in this transmission electron micrograph with proteins projecting from the viral envelope. Very many different variants of influenza have been identified since the virus was first discovered in 1935, and the variants are responsible for the different infections which occur in successive years. This is the reason that we can suffer from flu several times during our lives – in effect we become infected on each occasion with a different strain of virus, which our immune system has not encountered before and to which we are not immune.

Look at the overall structure of influenza A. The myxoviruses are all enveloped, that is to say that they have an outer membrane or envelope, which has been derived from the plasma membrane of an infected host cell. Two major viral proteins are present in the envelope, namely the haemagglutinin and the neuraminidase. Neuraminidase is an enzyme which cleaves sialic acid residues on glycoproteins and this protein performs an important function, in allowing the virus to bud off from the infected cell and spread through the body. The haemagglutinin is also essential for viral infection. It binds to carbohydrate groups present on glycophorins, molecules which occur on the surface of cells of the body. Binding of haemagglutinin to the surface of host cells is the first step in infection. Since the glycophorins are widely distributed on different cell types, influenza is able to cause widespread infection. As we shall see later, the antibody response against the haemagglutinin of the virus is critical in protecting us against on-going infection, although antibodies to the neuraminidase can also contribute to immunity. Within the viral envelope, the viral capsid is formed from the ‘M-protein’, which contains the virus’ genetic material, RNA, nucleoproteins, and a number of enzymes needed for replication.

The viral genome consists of 8 separate strands of RNA. Because the genome is fragmented in this way, it means that the different strains of virus can re-assort their genes relatively easily, and this is an important source of new viral strains.

Look now at the epidemic pattern of influenza over a number of years. The graph shows the number of isolates of different strains of influenza, in laboratories in the USA between 1995 and 1997. You can see that in temperate latitudes the infection rates follow a seasonal pattern, with more people developing the disease in the winter months. Examination of the structure of the haemagglutinin in successive years shows that minor mutations occur in the primary structure between the virus strains prevalent in each year. Although these do not affect the ability of the haemagglutinin to bind to host cells, the change is sufficient to prevent antibodies specific for a previous strain from binding to the new strain’s haemagglutinin. In effect, last year’s antibodies are unable to protect us from this year’s strain of flu.

The structure of the viral haemagglutinin can be seen in this model, which shows the backbone of the chain of amino acids. We will look at the way in which a neutralising antibody binds to an epitope on the haemagglutinin. The epitope is formed by amino acid residues in the loops at the exposed part of the molecule. Three loops which contribute residues to the epitope are highlighted here by space-filling the residues. Two domains of the heavy chain of the neutralising antibody are shown in yellow. The constant and variable domains are clearly visible, and the three hypervariable loops which contribute to the binding site are picked out in colour. You can see how the epitope and the heavy chain are complementary in shape. To complete the picture, we will add the light chain to the model. In this case, it is clear that the light chain contributes very little to the antibody combining site. When the space-filling model is completed, you can see that the residues forming the epitope are buried in the centre of the binding site and it is precisely these residues which are most likely to mutate between one viral strain and another. This progressive but limited change in the structure of the haemagglutinin is called genetic drift. Occasionally, perhaps once every 10–20 years, a major new strain of influenza appears which is radically different from those of previous years. Such a change is called genetic shift. The appearance of such new strains is associated with a worldwide serious epidemic of flu, called a pandemic. For example the pandemic strain of ‘Spanish flu’ which developed in 1918, had a different haemagglutinin and neuraminidase from the previously dominant strain, and this outbreak is thought to have caused the deaths of 20 million people world-wide. The picture shows a ward at the time. This epidemic particularly affected young fit people. One doctor wrote ‘it is only a matter of hours until death comes. It is horrible.’

The origin of new pandemic strains has been much debated, but it appears most likely that a human strain of flu exchanges genetic material with an animal strain of flu for example from ducks, or pigs. Such a reassortment of genes could occur if two different flu viruses simultaneously infect the same cell, and produce new viruses containing some gene segments from each type – remember that the flu virus has a segmented genome which allows this to occur.

The major pandemic strains are distinguished according to which haemagglutinin they have and which neuraminidase. So, for example in 1957 the dominant strain H1, N1 changed both its haemagglutinin and neuraminidase, and the new dominant strain H2N2 persisted until 1968. At present, (that is, in 2001) there are two dominant strains of influenza A in circulation H1N1 and H3N2.

One of the problems of producing vaccine for flu is that we do not know what next year’s major strain will be, and there is only a limited amount of time available before an epidemic spreads. The map shows the way in which the epidemic of Asian flu spread in 1957 from its origin in China in February, through South-East Asia by April and from there to all parts of the world by the end of the year. The figures on the map indicate the months in which the virus was isolated in different areas.

Nowadays, laboratories throughout the world track the appearance of new variants, and aim to identify the current circulating strains and any potentially new pandemic strains. Having decided the composition of the vaccine, there are just a few months to prepare it for the next flu season. Have a look at the current vaccine, it contains examples of the two major strains of influenza A H1N1 and H3N2 which are circulating and vaccine for the main current strain of influenza B. As there is insufficient time and resource to produce vaccine for everyone, the vaccine is usually recommended for older people and high risk groups, such as health professionals.

In addition to the antibody response, cytotoxic T cells are important in clearing virally-infected cells. The cytotoxic T cells recognise peptide fragments of several of the viral proteins, including the internal proteins such as the M-protein nucleoproteins and polymerases which are genetically stable. The bar chart shows the ability of lymphocytes from a single donor to kill cells which have been transfected with a single flu antigen. This is a measure of the prevalence of cytotoxic T cells for each of the proteins. Most of the cytotoxicity is directed against internal proteins shown on the green bars. Clones of cytotoxic cells against internal proteins usually recognise several of the major strains of flu. In contrast, those which recognise the external proteins are often, but not always strain-specific.

Even when a cytotoxic T cell recognises the same antigen as an antibody, it usually recognises a different portion. For example cytotoxic T cells specific for the haemagglutinin often recognise internal fragments of the antigen rather than the external epitopes recognised by antibodies. Moreover, since cytotoxic T cells recognise antigen presented by MHC molecules, and since MHC molecules are different in each individual, the T cells in each individual recognise different parts of the antigen. These bar charts show the response of two individuals against peptides from the haemagglutinin. T cells from the first person respond to four different regions of the molecule, with highly antigenic peptides centred on residues 100, 180, 300 and 400. T cells from the second individual recognise different regions of the haemagglutinin.

There is some evidence that individuals with specific MHC haplotypes may be more efficient than others at recognising and destroying influenza-infected cells.

In summary, influenza A gives us an example of extreme genetic variability, where successive dominant strains of flu emerge. The new strains are not susceptible to control by antibodies in the host population, and so individuals may suffer from repeated infections. Indeed the general immunity in the host population provides the selective pressure for the emergence of the new strains.

• Draw a labelled diagram of the structure of influenza A.
• How do pandemic strains of influenza A come about?

Your diagram should look like Figure 4 .

Pandemic strains of influenza A normally arise by simultaneous infection of a non-human host (typically poultry or pigs) with two or more strains of influenza A. Reassortment of the eight viral segments from each virus allows the generation of a new hybrid virus type, with a completely novel surface structure that has never been seen before by a host immune system (antigenic shift).

4 Antiviral treatments

Two classes of antiviral drugs are used to combat influenza: neuraminidase inhibitors and M2 protein inhibitors.

Why are antibiotics not used to combat influenza?

Influenza is a virus. Antibiotics only work against bacteria.

Neuraminidase inhibitors

Recall from Section 2.1 that neuraminidase is an enzyme that is present on the virus envelope and cleaves sialic acid groups found in the polysaccharide coating of many cells (especially the mucus coating of the respiratory tract). Neuraminidase is used to clear a path for the virus to a host cell and facilitates the shedding of virions from an infected cell. Inhibition of neuraminidase therefore helps prevent the spread of virus within a host and its shedding to infect other hosts.

The two main neuraminidase inhibitors currently in clinical use are zanamivir (trade name Relenza) and oseltamivir (trade name Tamiflu). These are effective against influenza A and B, but not influenza C which exhibits a different type of neuraminidase activity that only cleaves 9-O-acetylated sialic acid.

M2 inhibitors

Recall from Table 1 that the influenza M2 protein forms a pore that allows protons into the capsid, acidifying the interior and facilitating uncoating.

Drugs such as amantadine (trade name Symmetrel) and rimantadine (trade name Flumadine) block this pore, preventing uncoating and infection. However, their indiscriminate use in ‘over-the-counter’ cold remedies and farmed poultry has allowed many strains of influenza to develop resistance. Influenza B has a different type of M2 protein which is largely unaffected by these drugs.

5 Diagnosis of influenza

Many diseases produce symptoms similar to those of influenza; in fact, ‘flu-like’ is a term that is frequently used to describe several different illnesses. Since influenza spreads rapidly by airborne transmission and is a life-threatening condition in certain vulnerable groups, it is important that cases of the disease are identified as quickly as possible, so that preventative measures may be taken.

Most viral infections are not treated, although antiviral drugs such as zanamivir are used for potentially life-threatening cases or where the risk of transmission is high (as occurs during a pandemic).

Which sites in the body should be sampled for diagnosis?

The influenza virus infects the respiratory tract and is spread by coughing and sneezing, so specimens should be taken from the nose, throat or trachea.

In practice, the best specimens are nasal aspirates or washes, but swabs of the nose or throat may be used if they are taken vigorously enough to obtain cells. Ideally, samples should be taken within three days of the onset of illness, and all specimens need to be preserved in a transport medium and kept chilled until they reach the clinical microbiology laboratory.

5.1 Initial identification of influenza infection

Oral swabs or nasal aspirates are initially screened for the presence of a variety of respiratory viruses. This is done by extracting RNA from the sample and subjecting it to a reverse-transcription polymerase chain reaction (RT-PCR) as described below:

• Initially the RNA sample is reverse transcribed into complementary DNA (cDNA), using a commercially-available reverse transcriptase enzyme.
• The cDNA is then used in a standard PCR reaction to detect and amplify a short sequence of nucleotides specific to the virus. Multiple DNA sequences, each specific for a different type of virus, can be amplified in the same reaction, provided that these sequences are of different lengths.
• Each of the different amplified sequences is separated from the others when the entire sample is subjected to gel electrophoresis (an analytical technique in which molecules of different sizes move at various rates through a gel support in an applied electric field, thus making it possible to identify specific molecules.)

The polymerase chain reaction (PCR) technique is illustrated in Video 2.

Transcript: Video 2 PCR technique.

Polymerase chain reaction, or PCR, uses repeated cycles of heating and cooling to make many copies of a specific region of DNA. First, the temperature is raised to near boiling, causing the double-stranded DNA to separate, or denature, into single strands. When the temperature is decreased, short DNA sequences known as primers bind, or anneal, to complementary matches on the target DNA sequence. The primers bracket the target sequence to be copied. At a slightly higher temperature, the enzyme Taq polymerase, shown here in blue, binds to the primed sequences and adds nucleotides to extend the second strand. This completes the first cycle.

In subsequent cycles, the process of denaturing, annealing and extending are repeated to make additional DNA copies.

After three cycles, the target sequence defined by the primers begins to accumulate.

After 30 cycles, as many as a billion copies of the target sequence are produced from a single starting molecule.

Typically, nucleotide sequences specific to five types of virus are searched for in each sample: influenza A, influenza B, respiratory syncytial virus (Baltimore group V, (–)ssRNA virus, and a major cause of respiratory illness in young children), adenoviruses and enteroviruses. Those samples that test positive for influenza in the RT-PCR reaction are inoculated into cells in culture. Sufficient virus for a limited number of tests can be produced from such cultures within 24 hours, but they are often maintained for up to a week.

5.2 Determining the subtype of influenza

Immunofluorescence.

Confirmation of a case of influenza is usually achieved by performing tests on some of the inoculated cultured cells using reference fluorescent-labelled antisera provided by the WHO. A reference antiserum is a sample serum known to contain antibodies specific for the molecule to be assayed (in this case, haemagglutinin or neuraminidase). These antisera are prepared using purified haemagglutinin and neuraminidase and are monospecific, each antibody reacting only with one epitope e.g. H1 or H3.

For the test, an antibody is added to a sample of inoculated cells. Following a wash step, if the antibody remains bound to the cells then they fluoresce under appropriate illumination, indicating the presence of viral antigen on the cell surface. This diagnostic technique can identify influenza virus on infected cells in as little as 15 minutes. A positive result not only confirms the RT-PCR data, but gives additional information on the subtype of the virus.

Further PCR analyses

Standardised RT-PCR protocols exist to look for the presence of different haemagglutinin and neuraminidase subtypes, chiefly H1, H3, H5, N1 and N2. (Poddar, 2002). If the PCR analysis indicates a dangerous strain of influenza A e.g. H5N1, then it is instantly sent to a WHO reference laboratory for further tests.

Haemagglutination assays

Influenza has haemagglutinins protruding from its viral envelope, which it uses to attach to host cells prior to entry. These substances form the basis of a haemagglutination assay, in which viral haemagglutinins bind and cross-link (agglutinate) red blood cells added to a test well, causing them to sink to the bottom of the solution as a mat of cells. If agglutination does not occur, then the red blood cells are instead free to roll down the curved sides of the tube to form a tight pellet.

A related test called a haemagglutination-inhibition assay (HAI), incorporates antibodies against different subtypes of viral haemagglutinin. The antibodies bind and mask the viral haemagglutinin, preventing it from attaching to and cross-linking red blood cells.

A HAI assay can be set up in one of two ways: either a known reference antibody is added to an unknown virus sample, or known reference viral haemagglutinin is added to a sample of patient serum containing antibodies against influenza. This second version of the HAI assay can therefore be used long after the infection has passed, when virions are no longer present.

Haemagglutination and HAI assays have the advantage that they are simple to perform and require relatively cheap equipment and reagents. However, they can be prone to false positive or false negative results, if the sample contains non-specific inhibitors of haemagglutination (preventing agglutination) or naturally occurring agglutinins of red blood cells (causing agglutination).

If a confirmed influenza A isolate reacts weakly or not at all in HAI then this indicates an unknown variant of influenza A and the sample is immediately sent to a WHO reference laboratory for further tests.

Neuraminidase inhibition assay

Typing influenza isolates in terms of their neuraminidase makes use of the enzyme activity of this glycoprotein. The neuraminidase inhibition assay is performed in two parts. The first part determines the amount of neuraminidase activity in a patient influenza sample, as outlined in Figure 9a. A substrate (called fetuin) that is rich in sialic acid residues is added to a sample of the influenza virus, and the viral neuraminidase enzyme cleaves the substrate to produce free sialic acid.

Addition of a substance that inactivates the neuraminidase stops the reaction, and a chromogen (a colourless compound that reacts to produce a coloured end-product) that turns pink in the presence of free sialic acid is added. The intensity of the pink colour is proportional to the amount of free sialic acid and can be measured using a spectrophotometer.

This assay of neuraminidase activity allows the appropriate amount of virus sample to be determined, and this quantity is then used in the second part of the assay. If too much or too little virus is used, the resulting changes, and therefore the neuraminidase, may be undetectable.

In the second part of the assay (Figure 9b), viral samples from the patient are incubated with anti-neuraminidase reference antisera. Each of the reference antisera used for this test has antibodies that bind one particular neuraminidase variant, e.g. N1 or N2.

How can these antisera be used to type the neuraminidase variant?

If the antibodies bind the neuraminidase in the patient’s sample they inhibit its activity. This means that the patient’s neuraminidase cannot cleave the sialic acid from its test substrate fetuin, so no colour change will occur when the chromogen is added. Conversely, if the antibodies in the reference antiserum do not bind the neuraminidase in the patient’s sample, then the enzyme will remain uninhibited and the pink colour will be produced as before.

Part (a) of the diagram shows the sequence of obtaining a positive reaction in the neuraminidase inhibition assay. A patient sample containing influenza virus is added to the reaction well of a microtitre plate. Fetuin substrate is added, which is cleaved by viral neuraminidase into free sialic acid. A reagent is added that changes colour, dependent upon the amount of sialic acid present in the solution. Part (b) of the diagram shows how two different antibodies against neuraminidase can give two possible test outcomes for the patient sample from part (a). The diagram on the left shows what happens when the antibody binds to the neuraminidase and inactivates it (left side), while the right side diagram shows what happens when the antibody does not bind that type of neuraminidase. Fetuin and then the colour-change reagent are then added to both test wells. When the antibody fails to recognise the neuraminidase (right side) fetuin is cleaved by neuraminidase and gives a colour reaction. When the antibody recognises the neuraminidase (left side) its activity is blocked, fetuin is not cleaved and no colour reaction occurs.

6 Conclusion

As you reach the end of this free course you should consider some of the important points that the study of flu raises.

• A single pathogen can produce different types of disease in different people. Genetic variation in a pathogen can also affect the type of disease it produces. To understand this we need to know something of the genetic and social differences in the host population, and of the diversity of the pathogen.
• The symptoms of a particular disease may be produced by different pathogens or by a combination of pathogens. To understand this requires some knowledge of pathology and cell biology.
• Some diseases, such as flu, affect humans and several other animal species, whereas others are more selective in their host range. The basic biology of different pathogens underlies these differences.
• Flu is a disease that can be contracted several times during a lifetime, but many other infectious diseases are only ever contracted once. To understand this we need to look at how the immune system reacts to different pathogens, and how responses vary depending on the pathogen.
• Outbreaks of flu occur regularly, but some epidemics are much more serious than others. This requires an understanding of aspects of virology, immunology, evolutionary biology and epidemiology.

7 Questions for the course

The following questions allow you to assess your understanding of the content of this course. Each one relates to one or more of the intended learning outcomes of the study.

If you are unable to answer a question, or do not understand the answer given, then reread the relevant section(s) of the course and try the question again.

(This question relates to case study learning outcome (LO) 2.)

Why would Robert Koch have been unable to demonstrate that influenza viruses cause the disease influenza, according to his own postulates?

Koch’s second postulate states that the pathogen can be isolated in pure culture on artificial media. Viruses can only multiply within host cells, so Koch would have been unable to isolate the virus using artificial media. (Much later, eggs and live cells in tissue culture came to be used for growing flu virus, but this was long after Koch’s death, and they do not strictly conform to the original postulate.)

(This question relates to LO2.)

List the various structural components of an influenza A virus and note where each of these elements is synthesised within an infected cell.

Viral RNA is synthesised in the nucleus of the infected cell. The M-protein and other internal proteins are synthesised on ribosomes in the cytoplasm. The capsid is then assembled in the nucleus. The haemagglutinin and neuraminidase are synthesised on ribosomes on the endoplasmic reticulum. The envelope is derived from the host cell’s own plasma membrane.

(This question relates to LO2 and LO4.)

It is very uncommon for a strain of influenza that infects other animals to infect people; nevertheless such strains are very important for human disease. Why is this?

Animal strains of influenza act as a reservoir of genes that may recombine with human influenza viruses to produce new strains that can spread rapidly in humans. Such pandemic strains frequently produce serious diseases with high mortality.

(This question relates to LO2 and LO3.)

Which immune defences are able to recognise and destroy virally-infected host cells?

Cytotoxic T cells and NK cells are able to recognise and destroy virally-infected host cells.

(This question relates to LO4 and LO5.)

Why do most people suffer from influenza several times in their lives?

The virus mutates regularly (antigenic drift); also new strains are occasionally generated by recombination (antigenic shift). Since the immune response is generally specific for a particular strain of virus, new strains are not susceptible to immune defences which have developed against earlier strains.

Further reading

Acknowledgements.

This course was written by Jon Golding and Hilary MacQueen.

Except for third party materials and otherwise stated (see terms and conditions ), this content is made available under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 Licence .

Course image: thierry ehrmann in Flickr made available under Creative Commons Attribution 2.0 Licence .

The material acknowledged below is Proprietary and used under licence (not subject to Creative Commons Licence). Grateful acknowledgement is made to the following sources for permission to reproduce material in this course:

Figure 1: Prescott, L., Harley, J., and Klein, D. (1999) Microbiology, 4th ed. Copyright © The McGraw-Hill Companies

Figure 3: Noymer, A., and Garenne, M. (2000) ‘The 1918 influenza epidemic’s effects on sex differentials in mortality in the United States’, Population and Development Review , Vol 26 (3) 2000, The Population Council

Figure 6: CNRI/Science Photo Library;

Figure 7: Bammer, T. L. et al. (April 28, 2000) ‘Influenza virus isolates’ reported from WHO, Surveillance for Influenza – United States , Centers for Disease Control and Prevention

Video 1: Immunology Interactive (Male, Brostoff and Roitt) copyright the authors, reproduced by permission of David Male

Video 2: with kind permission from the Howard Hughes Medical Institute.

Every effort has been made to contact copyright owners. If any have been inadvertently overlooked, the publishers will be pleased to make the necessary arrangements at the first opportunity.

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Case Study: Unusual microbes

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Terminology

Epulopiscium, thiomargarita, small bacteria.

• Bacteria that give birth to live young

Square bacteria

Microbes with too much dna, microbes with too many genes, bacteria with "atypical" chromosomes.

• Bacteria that can count -- and talk

Bacteria that know where north is

Bacteria that eat other bacteria, multicellular bacteria, a huge virus, the biggest microbe, briefly noted, contributors, introduction.

This page was written in collaboration with Borislav Dopudja, a third-year science student at the University of Zagreb. It grew out of some casual but extensive discussions we were having exploring some of the oddities of the microbial world, things that don't quite fit with our common views. It seems worthwhile to share some of these. There is no attempt here to be profound, but rather to have some fun enjoying the diversity of the microbial world. Borislav's web site is: www.pluff-sky.net/. I have also listed it, with more information, on my page of Internet resources: Biology Miscellaneous in the Biology: other section.

What are "microbes"? Microbes (or microorganisms) are small organisms. For our purposes, that means single-celled organisms. The single cells may be prokaryotic or eukaryotic. The prokaryotic microbes include the bacteria and the archaea (or the eubacteria and archaebacteria, by older terminology). The eukaryotic microbes include the protists (protozoa), the fungi and at least the unicellular algae. The terms are not always used consistently, especially in older literature. Whether viruses should be included is a matter of taste, and I won't be entirely consistent there; for the most part, we will discuss cellular organisms.

Most of the links below are to web sites that are suitable for "the general audience". A few links to articles from the regular scientific literature are given in small type. In particular, in some cases I have included links to the first reports of these organisms or of key features.

Many links are to Microbe magazine -- or to its precursor, ASM News. Microbe is the news magazine of the American Society for Microbiology. Microbe is written for microbiologists, but written to be enjoyed by a wide range of non-specialists. Both the news stories and feature articles can serve well as readable material with serious scientific content, yet not too technical. Microbe is now freely available online. Links to individual items are given as they come up. If you would like to browse Microbe magazine -- recommended! -- go to http://www.microbemagazine.org/ . The current issue will come up; for more, see "Explore Microbe" at the left.

Some links are given to original articles or news stories in Science magazine. Some of these are freely available online, though you may need to create a free registration before getting access to the full text. In general, Science releases research articles -- but not news stories -- for free access 12 months after publication; their file goes back to about 1997. (Those with institutional subscription access, such as those using university computers at UC Berkeley, have full access, and will not be asked to register or log on.) The home page for Science magazine: http://www.sciencemag.org .

Big bacteria

One of the most characteristic properties of bacteria is that they are small. Microscopic. Barely visible under the microscope: we can tell their general shape, but can generally see very little structure. Typical dimensions are on the order of 1 micrometer (1 μm). So, have a look at Epulopiscium and Thiomargarita -- bacteria big enough to be seen with the naked eye. These bacteria -- at least the larger specimens -- approach 1 millimeter (1 mm) in size. One of these was first reported in 1985 -- but not understood to be a bacterium until 1993; the other was first reported in 1999.

Epulopiscium grows in the gut of certain fish. It has a complex life cycle, which is coordinated with the daily rhythm of its host. This complex -- and unusual -- life cycle qualifies Epulopiscium for another section of this page: Bacteria that give birth to live young .

• http://microbewiki.kenyon.edu/index.php/Epulopiscium . From the Microbe Wiki.
• www.microbelibrary.org/index....ium-fishelsoni. From the Microbe Library at ASM.
• www.accessexcellence.org/LC/ST/st12bg.php. "Epulopiscium fishelsoni, Big bug baffles biologists!", an essay on this unusual bug, from Peggy E Pollak & W Linn Montgomery, both early investigators of Epulos. (Another Access Excellence page is listed on this page, in the section The biggest microbe? . The Access Excellence site is listed as a general resource on my page of Miscellaneous Internet Resources, under Of local interest... -- since it had its origins near here.)

Cornell researchers study bacterium big enough to see -- the Shaquille O'Neal of bacteria . Press release (May 6, 2008) on new work showing that an Epulopiscium cell contains 100,000 or so copies of its genome, thus has many times more DNA than a human cell. This site is worth it for the pictures alone. The upper picture is a classic, showing an Epulo, a paramecium and an ordinary E. coli bacterium. http://www.news.cornell.edu/stories/...cteria.kr.html . The paper, from Angert's lab at Cornell and collaborators in Australia and New Zealand, is: J E Mendell et al, Extreme polyploidy in a large bacterium. PNAS 105:6730-6734, 5/6/08. Online: http://www.pnas.org/content/105/18/6730.abstract .

The first report of Epulopiscium, describing it as a large and peculiar cigar-shaped organism, presumably a protist: L Fishelson et al, A unique symbiosis in the gut of tropical herbivorous surgeonfish (Acanthuridae: Teleostei) from the Red Sea. Science 229:49, 7/5/85. The abstract is freely available at http://www.sciencemag.org/content/22...08/49.abstract . You may or may not be able to get the full article at that site. If not and you have an institutional subscription to JStor, such as at UCB, try www.jstor.org/stable/1695432. The definitive report that Epulopiscium is really a bacterium: E R Angert et al, The largest bacterium. Nature 362:239, 3/18/93. http://www.nature.com/nature/journal.../362239a0.html .

Thiomargarita can be quite big, but it "cheats". It is mostly vacuole. Why? Well, it is quite like a deep sea diver carrying an oxygen tank. Thiomargarita uses nitrate ions in its respiration, rather than oxygen gas; the vacuole is a supply of nitrate that lets the bug continue to respire at great depths.

Is Life Thriving Deep Beneath the Seafloor? An article from the Woods Hole Oceanographic Institute (WHOI). http://www.whoi.edu/oceanus/viewArticle.do?id=2497 . To focus on Thiomargarita, scroll down to "The world's largest bacterium". The article is by WHOI oceanographer Carl Wirsen, April 2004. WHOI microbiologist Andreas Teske was part of the team that discovered Thiomargarita; he is a co-author of the Science paper listed below as the original report.

The original report on Thiomargarita: H N Schulz et al, Dense populations of a giant sulfur bacterium in Namibian shelf sediments. Science 284:493, 4/16/99. It is accompanied by a news story: B Wuethrich, Microbiology: Giant sulfur-eating microbe found. Science 284:415, 4/16/99. The article is freely available at: http://www.sciencemag.org/content/28...3/493.abstract .

Scientists from UC Berkeley, led by Dr Jill Banfield, have found an archaeon smaller than any cellular organism previously known. It is about 200 nm (0.2 μm) diameter. It is so small that it is very near the "limit" of what people think might be the smallest possible organism. In fact, some people think it might be below that limit! Time will tell whether the new claim is valid. An important issue is whether this is a "complete" organism, or a parasite of some kind that is absolutely dependent on other cells to provide basic functions. This is part of their work on the acidic mine drainage from the Richmond Mine at Iron Mountain, Calif.

Shotgun sequencing finds nanoorganisms. A news release from UC Berkeley, December 2006, on this discovery: http://www.berkeley.edu/news/media/releases/2006/12/21_microbes.shtml . The original report on this tiny organism: B J Baker et al, Lineages of acidophilic archaea revealed by community genomic analysis. Science 314:1933, 12/22/06. http://www.sciencemag.org/content/31.../1933.abstract .

There is another story of small bacteria, a story that has been around for several years but has not really been confirmed. The basic idea is a claim that there are tiny bacteria involved in such processes as calcification of your arteries. These bacteria, which have been termed nanobacteria , are alleged to be even smaller than those discussed above -- far below any reasonable limit of what is "possible" for a living cell. Since these alleged organisms really do not fit in any modern understanding of what cells are, solid evidence is needed -- and is lacking. Two new papers appeared in early 2008 with rather strong evidence that these "things" are not alive. They appear to be some calcium minerals, complexed with protein. They may well be interesting, and they may still be involved in disease processes, but they are not bacteria. The Wikipedia entry is a good introduction to these "nanobacteria" (or "calcifying nanoparticles"), including the uncertainties that surround them. It notes these 2008 papers, and has links to them, and to one good news story on the new findings. http://en.Wikipedia.org/wiki/Nanobacterium .

Bacteria divide by binary fission: they grow bigger, and then divide in two. But there are exceptions. An interesting type of exception occurs when bacteria seem to give birth to live young. That is, they develop new cells inside, and then liberate these daughter cells. One of the first cases where this type of bacterial reproduction was seen was with Epulopiscium, discussed in the section on Big bacteria . Then it was found in the bacterium Metabacterium -- but in a form that was easier to understand. It has long been known that some bacteria make spores. Specifically, bacteria of the genera Bacillus and Clostridia make "endospores": each cell makes one spore, a resistant structure that is capable of long term survival. Such spore formation does not increase the population, because each cell makes one spore. It merely results in a new type of cell, the resistant spore. But Metabacterium makes multiple spores per cell -- and rarely undergoes the more "ordinary" process of binary fission. Thus a variation of ordinary endospore formation has become the primary means of reproduction. With Epulopiscium, it would seem that this process has been modified further, so that what is produced is not spores but rather ordinary cells -- baby cells.

Thus both Metabacterium and Epulopiscium "give birth to live young" -- a process that can be thought of as a variation of ordinary endospore formation.

Esther Angert, Beyond binary fission: Some bacteria reproduce by alternative means. Microbe 1:127, 3/06: forms.asm.org/microbe/index.asp?bid=41230 (HTML) or forms.asm.org/ASM/files/ccLib...0306000127.pdf (PDF). Angert, at Cornell, works with both Metabacterium and Epulopiscium. She was the first to recognize that Epulopiscium was actually a bacterium.

Metabacterium with four daughter spores . The figure at the right shows a single Metabacterium polyspora cell containing four spores, with the bright appearance that is typical of bacterial endospores. The individual spores are several μm long. The figure is a trimmed version of a figure at: author.cals.cornell.edu/cals/...abacterium.cfm. That page discusses the life cycle of Metabacterium, and how it relates to the natural environment for this organism. It is part of Esther Angert's web site; the home page is author.cals.cornell.edu/cals/...-lab/intro.cfm.

More links for Epulopiscium are in the section on Big bacteria .

What is the shape of bacteria? Round. Or roundish -- such as rods with rounded ends. Certainly not square, with sharp corners. Imagine then the surprise of the scientist who, in 1980, found square bacteria with sharp corners, in concentrated salt solutions. They are not only square, but very thin -- about 200 nm (0.2 μm) thick. They seem to grow as two dimensional objects, increasing the size of their squares, but not their thickness. Square bacteria caught in the act of division look like a sheet of postage stamps.

Their thinness increases their surface to volume ratio; this may be important in helping them to maintain a proper intracellular environment. They probably spend much energy pumping ions out!

It is not known why they are square or how they achieve their squareness. The square bacteria are archaea. (That was recognized in the original report; at that time, the archaebacteria were considered a type of bacteria, whereas we now consider them a distinct group from the bacteria per se.) They have been named Haloquadratum walsbyi.

The following two links both include good pictures of the square bacteria. The figure at the right is a variation of one shown at the second site, Dyall-Smith's web site.

• Square bacteria grown in the laboratory. Press release, from the University of Melbourne, announcing the first successful growth of the square bacteria in the lab, October 2004. uninews.unimelb.edu.au/news/1855/.
• Web site for Dr Mike Dyall-Smith, group leader for that work: http://www.haloarchaea.com/ . The broad topic of the site is Haloarchaea and Haloviruses.

Edwin Abbott would have loved them. http://www.ibiblio.org/eldritch/eaa/FL.HTM . A good read!

Genome paper: H Bolhuis et al, The genome of the square archaeon Haloquadratum walsbyi: life at the limits of water activity. BMC Genomics 7:169, 7/4/06. Free online: http://www.biomedcentral.com/1471-2164/7/169 . The original report of these organisms: A E Walsby, A square bacterium. Nature 283:69, 1/3/80. It's a delightful little paper, a brief report of a quite unexpected observation. Online: http://www.nature.com/nature/journal.../283069a0.html . Even reading the opening lines, which are freely available there, gives a nice hint of the literary quality of this paper. However, it probably requires subscription for full access.

The organism with the largest known genome? Amoeba dubia, a protist. 670 billion base pairs of DNA. That is about 200 times more than we have. What is the significance of this finding? It's not at all clear. In fact, it is hard to even find the source of the number. Is this really a measure of the haploid genome size? Or is it simply based on the cellular DNA content, with the assumption that the cell is diploid? Not only is the original source hard to pin down, there seems to be no modern work following it up. But the number is oft-quoted, so we quote it too. Someday we may understand what it means.

For a nice discussion of genome sizes, see http://www.genomesize.com/statistics.php . Scroll down to the section "A comment on the overall animal range", and what follows, including a nice graph summarizing genome sizes over all types of organisms. This is from T Ryan Gregory, Univ Guelph. Regardless of the ultimate verdict on the Amoeba dubia genome, many organisms have genomes much larger than ours.

In the web page referred to above, Gregory gives genome size in picograms (pg). Biologists often give genome sizes in base pairs (bp). 1 picogram of DNA is about 10 9 (one billion) base pairs. For example, the human genome contains about 3.5 billion bp, and weighs about 3.5 pg. Gregory's genome size site is also referred to on my Internet resources - Molecular Biology page, under Genomes , and in the Musings post Who is #1: the most DNA? (March 7, 2011) .

The human genome project brought us the revelation that we have only about 22,000 genes -- not all that many more than a worm (Caenorhabditis elegans, 20,000 genes) or a fruit fly (Drosophila melanogaster, 14,000 genes). Now, Trichomonas vaginalis - a common sexually-transmitted protist (protozoan)... Its genome sequence was reported in January 2007. Preliminary analysis suggests about 60,000 genes.

Don't make too much of this. Gene counts are notoriously difficult, as we learned from the human genome project. Identification of genes simply by looking at DNA sequences is something of an art. In fact, the report offers multiple numbers for the gene count, using different criteria. Of course, I chose the higher one for this note. Further, the significance of the gene count is unclear. We now understand that many proteins can be made from a "single" gene (for example, by alternative splicing). Nevertheless, this stands, at least for now: the most genes known in any microbe, in fact, in any organism. Glossary entry: Alternative splicing .

News story in Microbe, 4/07: "Peculiar" T. vaginalis parasites are jam-packed with genes. forms.asm.org/microbe/index.asp?bid=49481.

Scientists Crack the Genome of the Parasite Causing Trichomoniasis. The press release from the New York Univ School of Medicine, one of the lead institutions for this work. January 11, 2007. http://communications.med.nyu.edu/ne...trichomoniasis .

The report of the Trichomonas genome: J M Carlton et al, Draft genome sequence of the sexually transmitted pathogen Trichomonas vaginalis. Science 315:207, 1/12/07. Online: http://www.sciencemag.org/content/315/5809/207.short .

In the early days, it was very difficult to observe bacterial chromosomes. Bacteria are small, and their chromosomes are quite tiny by comparison with eukaryotic chromosomes. Further, bacterial chromosomes do not condense into more compact and more easily visible bodies, again in contrast to eukaryotic chromosomes. So, information about bacterial chromosomes emerged slowly, with various -- and mostly indirect -- techniques.

The early work suggested that bacteria have only one chromosome, and that it is circular. In one case, one E coli chromosome was even observed -- a circle. Other work seemed consistent with this, so the generality emerged: bacteria have only one chromosome, and it is circular. Both of these features served to distinguish bacteria from the eukaryotes. And that was nice: bacteria are supposedly "simpler", and having only one chromosome is certainly "simpler". Further, having a circular chromosome avoided the difficulties of replicating linear DNA, and could also be considered "simpler".

Alas, it is not really so. Neither feature is universal among bacteria. This web site discusses bacterial chromosomes, and has a table showing the number and type of chromosomes found in many bacteria. http://www.sci.sdsu.edu/~smaloy/MicrobialGenetics/topics/chroms-genes-prots/chromosomes.html . From Stanley Maloy, San Diego State University. It is part of a larger site on the broader topic of microbial genetics: http://www.sci.sdsu.edu/~smaloy/MicrobialGenetics/ .

The following site is from a discussion of bacterial genetics in an online microbiology textbook. I include it here particularly because it contains a nice copy of a very famous figure, which I referred to above. Go to http://www.ncbi.nlm.nih.gov/books/NBK7908/ ; scroll down to Fig 5.2. This shows a single chromosome of one E coli cell, in the act of replicating. It is clearly circular.

That site is from Chapter 5, Genetics, by R K Holmes & M G Jobling, of the online book Medical Microbiology, 4th edition, edited by S Baron. This online book is listed in the Microbiology: books section of my page of Internet resources: Biology - Miscellaneous. The figure is from John Cairns, Cold Spring Harbor Symposia on Quantitative Biology 28:44, 1963.

Some bacteria can emit light -- more or less as fireflies do. The phenomenon is called bioluminescence. But the light from a single bacterial cell would be too dim to be of any use. So, isolated bacteria do not emit light. They only emit light when there are many of them together, so that -- together -- they give off a substantial amount of light. Clearly, bacteria can count how many neighbors they have.

How do bacteria count their population size? The basic logic of how they do it is actually rather simple. To make light, they need an "inducer" -- a substance that turns on the light-producing system. They make an inducer, and secrete it into the external environment. They then take it up from the environment. What does this accomplish? Well, imagine a simple situation of bacteria growing in a test tube. If there are only a few bacteria, there will be little inducer in the tube. When the bacteria try to take up inducer from the environment, they find very little -- and thus they do not emit light. But if the bacteria grow, so that there are many many bacteria in the tube, all making and secreting inducer, then the bacteria find a high level of inducer in the environment; they take it up, and emit light. Thus the bacteria sense their population size by responding to the level of inducer in the medium; as a result, they emit light only when the population size is large.

Is that artificial situation of a test tube of bacteria relevant to the bacteria in nature? Indeed it is. Some fish cultivate these bacteria in a special pouch, called a light organ. The light organ emits light only when it contains enough bacteria to do so usefully.

The phenomenon discussed above is often called quorum sensing . That is, the bacteria check to see if a quorum is present before emitting light. The details of this are now quite well understood. And as the system was being studied, it became clear that it was simply one example of a much wider phenomenon: bacteria communicating to each other, for a range of purposes. In this case, the bacteria are communicating their population size to their own kind. But more broadly, bacteria are signaling their presence -- and numbers -- to other types of bacteria too.

What is the highest temperature at which life is possible? We all know that many of the molecules in living systems are quite sensitive to heat; the ease of cooking an egg reminds us of that regularly.

When I was in college, the highest temperature reported for life was around 60° C (degrees Celsius), the maximum temperature (T max ) for growth of the bacterium Bacillus stearothermophilus. Since then, the known maximum has increased to at least 113° C, and perhaps even to 121° C. This increase came along with the discoveries of an entirely new class of microorganism, the archaea, and of a new geological phenomenon, the deep sea thermal vent; both discoveries date from 1977. Thus the increase in known T max for life is not simply an abstract story of some biological limit, but is part of a broad series of major advances in both biology and geology.

Thermus aquaticus has a maximum growth temperature of about 80° C. It was isolated from hot springs in Yellowstone National Park, and was reported in 1969. Thermus aquaticus is perhaps the organism that ushered in the new era of the commercialization of enzymes from thermopiles -- useful precisely because of their heat stability; the "Taq" DNA polymerase made the polymerase chain reaction -- PCR -- practical.

As noted above, 1977 brought the separate discoveries of archaea and deep sea thermal vents. Over the following years, these stories converged, and a succession of hyperthermophilic archaea were discovered near the vents. 1997 brought Pyrolobus fumarii, which grows up to 113° C; this archaeon has been widely accepted as having the highest known T max . 2003 brought a report of an archaeon that could grow at 121° C -- the normal operating temperature of an autoclave commonly used to kill even the most resistant forms of life, or so we thought. This organism has been dubbed simply Strain 121 for now.

These continuing discoveries of organisms with ever higher T max , maybe even up to the common operating temperature of an autoclave, raise some questions: ... [ more ]

Derek Lovley's web page (Univ Massachusetts) on the work that led to Strain 121: www.geobacter.org/Life-Extreme.

The first report of Strain 121. K Kashefi & D R Lovley, Extending the upper temperature limit for life. Science 301:934, 8/15/03. Online at http://www.sciencemag.org/content/301/5635/934.full . For more about Lovley's lab, see "Electricigenic bacteria" in either the Redox section of the page for Internet resources for Intro Chem or the Carbohydrates section of the page for Internet resources for Intro Organic/Biochem. For an update, see a summary of the Ninth International Conference on Thermophiles (Bergen, Norway, September 2007). T Satyanarayana, Meeting report: Thermophiles 2007. Current Science 93(10):1340, 11/25/07. Current Science, published by the Indian Academy of Sciences is freely available online. This article is at: http://www.ias.ac.in/currsci/nov252007/1340.pdf . The article contains a number of interesting tidbits. They suggest that the finding that strain S121 grows at 121° C has been questioned; they also suggest that another microbe has been shown to grow at 122° C at high pressure. It is normal enough that such claims are questioned. Time will tell. None of these details change the general perspective on high temperature microbes presented here.

A microbiologist looks at a sample under the microscope. He notices that the bacteria seem to be moving over to one side of the microscope slide. Why? Perhaps they are responding to the light. So he adjusts the lighting, and it has no effect. After numerous such observations and tests, the conclusion is inescapable: the bacteria go north. Now, that is novel! He looks at the bacteria further, and finds that they contain tiny magnets -- iron oxide magnets, just like simple toy magnets. And that is how magnetic bacteria were discovered -- by Richard Blakemore in 1975.

Why do these bacteria use a magnet to guide their swimming? A common idea -- not entirely accepted -- is that these bacteria benefit from following the earth's magnetic lines of force. Doing that leads them "down" into the mud, which seems good for their lifestyle. Consistent with this, it was soon found that -- for some types of magnetic bacteria -- those in the northern hemisphere swim north, whereas those in the southern hemisphere swim south.

Magnetic Microbes , by Sandi Clement. commtechlab.msu.edu/Sites/dlc.../caOc96SC.html.

Magnetosomes . The figure at the right is from Richard Frankel's page: Magnetotactic Bacteria Photo Gallery. www.calpoly.edu/~rfrankel/mtbphoto.html. The figure shows a single cell of the bacterium Magnetospirillum magnetotacticum, with a chain of magnetosomes. Each individual magnetosome in the chain is approximately 45 nm across, and surrounded by a membrane. The Gallery page listed has many more figures, showing the diversity of magnetic bacteria. And for more, go to Frankel's home page, at Cal Poly San Luis Obispo: www.calpoly.edu/~rfrankel/. Scroll down to Research Interests, then Magnetotactic Bacteria.

R B Frankel & D A Bazylinski, Magnetosome mysteries. ASM News 70:176, 4/04. The news magazine ASM News -- now called Microbe -- is free online; this item is at forms.asm.org/microbe/index.asp?bid=26445.

C N Keim et al, Magnetoglobus, Magnetic aggregates in anaerobic environments. Microbe 2:437, 9/07. Microbe, the news magazine of the American Society for Microbiology is free online; this item is at forms.asm.org/microbe/index.asp?bid=52638. An article about a type of magnetic bacterium that normally occurs in multicellular aggregates. Should this be considered a multicellular bacterial organism? Considering that question gives insight into what multicellularity is about. This article is also listed in the section Multicellular bacteria .

W Hansen, This End Up -- Magnetic organelles point bacteria in the right direction. Berkeley Science Review, Issue 14, Spring 2008, p 8. A brief introduction to work on magnetic bacteria being done by Arash Komeili at UCB. Berkeley Science Review (BSR), published by UCB graduate students, is free online; this item is at sciencereview.berkeley.edu/ar...ticle=briefs_1.

The first report of magnetic bacteria: R Blakemore, Magnetotactic bacteria. Science 190:377-379, 10/24/75. The abstract is freely available at http://www.sciencemag.org/content/190/4212/377.abstract . You may or may not be able to get the full article at that site. If not and you have an institutional subscription to JStor, such as at UCB, try Access to Blakemore article through JStor.

The story of predatory bacteria starts with Bdellovibrio , a type of bacterium that obligatory lives within other bacterial cells. Since they kill the bacteria that they infect, Bdellovibrios form clear regions on a lawn of dense bacterial growth, much like bacterial viruses form plaques. But they are not viruses. They are cellular, with rather ordinary bacterial cells. It's just that they grow in a way that we find unusual. Well, it's not the "way" that is unusual as much as it is the "where". They burrow into a bacterial cell, and grow there.

E Jurkevitch, Predatory behaviors in bacteria -- diversity and transitions. Microbe 2:67, 2/07. Microbe, the news magazine of the American Society for Microbiology, is free online; this item is at forms.asm.org/microbe/index.asp?bid=48203.

At the end of the article listed above, Jurkevitch raises an interesting speculation about the possible role of predatory bacteria in the origin of the eukaryotic cell. Biologists agree that the mitochondrion arose from a bacterium that got inside another cell. But how did it get there? Bacteria do not show phagocytosis -- do not engulf other cells. However, predatory bacteria such as Bdellovibrio offer an alternative. Perhaps mitochondria originated by a predation event that led to symbiosis. There is no evidence on this point, so it must be regarded as speculation for now. At least it is a plausible view of how one of the great events of biological history might have occurred.

Single cells. Grow, and then divide into two. That is our simple image of bacteria. However, as we learn more about this vast group of organisms, we find that bacteria can be more complex. The myxobacteria probably have the most complex bacterial life cycle. They spend part of their life as free-living individual bacterial cells, then aggregate to form a fruiting body, an organized multicellular structure visible to the naked eye. In fact, their life cycle is rather similar to that of the cellular slime molds, such as Dictyostelium -- the myxomycetes.

Myxobacteria web page : http://myxobacteria.ahc.umn.edu/ . In particular, step through the section What are the Myxobacteria? for a good introduction with some wonderful pictures. From Dr Martin Dworkin, with the help of Tim Leonard, at the University of Minnesota.

M Dworkin, Lingering Puzzles about Myxobacteria . Microbe 2:18, 1/07. Dworkin's "puzzles" include:

• How the cells construct the multicellular, macroscopic fruiting body
• The biochemical basis of myxospore morphogenesis
• The mechanism and function of individual cellular motility
• The regulation of directionality of social movement
• The mechanism of the cells' ability to perceive physical objects at a distance
• The role of the myxobacteria in nature.

Microbe, the news magazine of the American Society for Microbiology, is free online; this item is at forms.asm.org/microbe/index.asp?bid=47794 (HTML) or forms.asm.org/ASM/files/ccLib...0107000018.pdf (PDF).

C N Keim et al, Magnetoglobus, Magnetic aggregates in anaerobic environments. Microbe 2:437, 9/07. Microbe, the news magazine of the American Society for Microbiology is free online; this item is at forms.asm.org/microbe/index.asp?bid=52638. An article about a type of magnetic bacterium that normally occurs in multicellular aggregates. Should this be considered a multicellular bacterial organism? Considering that question gives insight into what multicellularity is about. This article is also listed in the section Bacteria that know where north is . Other topics on this page introduce other ways in which some bacteria are more complex that we might have thought. These include:

Ordinary organisms are based on cells. The organisms reproduce by the cells growing and dividing. Viruses are different. Viruses are small and simple. Viruses do not grow and divide. They reproduce by infecting a cell, disassembling, and then directing the production of new "parts", which then assemble into new virus particles.

Small and simple? Well, usually. The smallest viruses have one millionth or so the amount of genome (DNA or RNA) we do. Some have only a handful of genes. Some have only a piece of DNA (or RNA) and a simple protein coat -- no machinery for making anything, and no enzymes.

Some viruses are not so small and not so simple. Biologists have still been able to make a clear distinction between viruses and cells, primarily by looking at their basic strategy for reproduction. Cells grow and divide; viruses disassemble and reassemble.

The most recent challenge to the simplicity of viruses is the mimivirus , which grows in the protozoan Acanthamoeba polyphaga. It has about three times more genetic material (DNA) than any previously known virus -- more DNA than some bacteria. It is bigger than some bacteria -- about 400 nm (0.4 μm) diameter. And it is quite complex, with a collection of enzymes that are supposedly not to be found in viruses. For example, mimivirus codes for several enzymes used in protein synthesis -- genes never before found in any virus. Yet its life style (and structure) make it clear that this is a virus. It was characterized as a virus only in 2003.

2008 brings new developments that make the story of mimivirus even more fascinating. First, a new mimivirus, even bigger than the first. They call it mamavirus. But perhaps more importantly, a satellite virus: a virus that can grow only in cells infected by mimivirus. A news story about this satellite virus, dubbed Sputnik: 'Sputnik' Virus Orbits, Hijacks Other Viruses, Aug. 13, 2008. dsc.discovery.com/news/2008/0...s-sputnik.html.

Discussions about mimivirus and Sputnik inevitably seem to wander onto topics such as "What is a virus?" or even "What is life?" These are fun to discuss, but a caution: they need not have simple answers, or even any answers at all beyond our common definitions. Use such questions to provide a framework for your knowledge and understanding, but forcing simple answers to complex questions is not fruitful. Mimivirus has its own website: http://www.giantvirus.org .

The organism now known as mimvirus was found in 1992. The first paper that identified it as a virus: B La Scola et al, A giant virus in Amoebae. Science 299:2033, 3/28/03. Online: http://www.sciencemag.org/content/299/5615/2033.short . The report of the Sputnik satellite virus: B La Scola et al, The virophage as a unique parasite of the giant mimivirus. Nature 455:100, 9/4/08. There is a good news story about this finding: Biggest known virus yields first-ever virophage. Microbe 3:505, 11/08. Free online: microbemagazine.org/images/st...1108000502.pdf. Scroll down to the story, on page 4 of the file.

Probably the unicellular green alga Acetabularia , whose cells can be several centimeters long. Because of the large size, Acetabularia was a favorite organism for studying the relationship between nucleus and cytoplasm. The following links introduce the organism and some classic experimental work.

• en.Wikipedia.org/wiki/Acetabularia. Basic introduction to Acetabularia.
• www.accessexcellence.org/RC/V...mmerling_s.php. Classic work on the role of nucleus and cytoplasm in determining cell development, done by J Hammerling in the 1930s. The large cells of Acetabularia allowed a simple but novel transplantation to be done; the results revealed the key role of the nucleus. This item is given as a link at the end of the previous one. (Another Access Excellence page is listed on this page, in the section Big bacteria . The Access Excellence site is listed as a general resource on my page of Miscellaneous Internet Resources, under Of local interest... -- since it had its origins near here.)

This section is something of a "miscellany" -- a place to briefly note some other unusual aspects of microbial life. In some cases, I may make only a single small point or note only a single paper, Perhaps some of these will grow into "full-blown" topics at some point, or perhaps we will just keep a section of "miscellany".

G forces? Humans don't do well with g forces a few times normal gravity. Microbes do better, it seems. A recent paper shows that several microbes studied, bacteria and yeast, grew in an ultracentrifuge tube with accelerations many thousands of times g. Two of the bacterial grew at the highest accelerations tested, over 400,000 x g. They have no information about what limits the growth as the g force increases; they speculate that it has something to do with sedimentation within the cell. That organisms vary might allow them to pursue finding what is important. It is also unclear why this is of interest. After all, such high g forces are found in nature only under extreme conditions, such as the shock waves of supernovae. For now, this paper is basically just a cute finding. It will be interesting to see where it leads.

• News story... Bacteria Grow Under 400,000 Times Earth's Gravity (National Geographic, April 25, 2011): http://news.nationalgeographic.com/news/2011/04/110425-gravity-extreme-bacteria-e-coli-alien-life-space-science/ .
• The paper... S Deguchi et al, Microbial growth at hyperaccelerations up to 403,627 x g. PNAS 108:7997, May 10, 2011. Online at: http://www.pnas.org/content/108/19/7997 .

Where is the inside? Some bacteria, such as the gram negatives, have a double membrane system. It is the inner membrane that is energized, and used to make ATP. Now we have a discovery of the first double membrane system of an archaeon -- and it is the outer membrane that is energized. The archaeon, Ignicoccus hospitalis , is closely associated with Nanoarchaeum equitans -- which relies on the Ignicoccus for its energy; is this energy parasitism dependent on the unusual energy system of the Ignicoccus? The authors even wonder whether Ignicoccus might be an ancestor of the eukaryotic cell. Clearly, this is an unusual and intriguing finding -- still quite incomplete.

For a fine introduction to this novel system, see the ASM blog entry by Moselio Schaechter... Of Archaeal Periplasm & Iconoclasm (February 11, 2010): http://schaechter.asmblog.org/schaechter/2010/02/of-archaeal-periplasm-iconoclasm.html .

The paper... U Küper et al, Energized outer membrane and spatial separation of metabolic processes in the hyperthermophilic Archaeon Ignicoccus hospitalis . PNAS 107:3152, 2/16/10. Online at: http://www.pnas.org/content/107/7/3152 .

Arsenic . There are bacteria that can oxidize arsenic compounds, and there are bacteria that can reduce arsenic compounds. Now there is a report of bacteria that can use arsenite -- AsO 3 3- , containing As(III) -- as the electron donor for photosynthesis. (The most common electron donor is water -- with oxygen gas being evolved. The most common electron donor in anaerobic systems is sulfide, often with sulfur granules being produced.) Analysis of this process suggests that arsenic metabolism is quite ancient, and that it is an important part of the arsenic cycle in nature. News story: In Lake, Photosynthesis Relies on Arsenic, August 18, 2008. http://www.nytimes.com/2008/08/19/science/19obarsenic.html .

The paper... T R Kulp et al, Arsenic(III) Fuels Anoxygenic Photosynthesis in Hot Spring Biofilms from Mono Lake, California. Science 321:967, 8/15/08. Online at: http://www.sciencemag.org/content/321/5891/967.abstract .

Microbes survive the cold . Scientists have recovered DNA and even viable bacteria from ancient ice samples in the Antarctic (and other places). The idea is that bacteria were trapped in the ice, perhaps in pockets of liquid water just big enough for the one cell. The bacteria may have carried out maintenance reactions, perhaps only a few chemical reactions per day, to survive. Even with quibbling about how old each sample really is, this is still a fascinating insight into survival of life in extreme conditions. News story: Eight-million-year-old bug is alive and growing, August 7, 2007. http://www.newscientist.com/article/dn12433 .

Here are a couple of papers, both of which should be freely available. The first goes with the news story listed above, and is generally about the isolation of the old bacteria and their DNA. The second, from UC Berkeley, is about how the bacteria may metabolize and survive in the ice. K D Bidle et al, Fossil genes and microbes in the oldest ice on Earth. PNAS 104:13455, 8/14/07. Free online at: http://www.pnas.org/content/104/33/13455.abstract . R A Rohde & P B Price, Diffusion-controlled metabolism for long-term survival of single isolated microorganisms trapped within ice crystals. PNAS 104:16592, 10/16/07. Free online at: http://www.pnas.org/content/104/42/16592.abstract .

A lonely bug . Organisms live in complex communities. Seems pretty basic in our modern understanding of biology. Certainly, we expect to find bacteria in complex communities. So, it is striking when we find a report of the discovery of a bacterial growth in a South African goldmine that seems to contain only one species. Of course, it is hard to exclude some very low level of other organisms, but the analysis shows that the main bacterium, called Candidatus Desulforudis audaxviator, is at least 99.9% of the culture.

What is it growing on down there? Well, seems likely that it is using the energy from uranium decay as its main energy source. So this loner is also a nuclear-powered bug.

The paper is: D. Chivian et al, Environmental Genomics Reveals a Single-Species Ecosystem Deep Within Earth . Science 322:275, 10/10/08. Free online at: http://www.sciencemag.org/content/322/5899/275.abstract . For a good news story about this work, see Journey Toward The Center Of The Earth: One-of-a-kind Microorganism Lives All Alone , 10/10/08: http://http://www.sciencedaily.com/releases/2008/10/081009143708.htm .

More "Curious microbes"

While looking for some nice web sites to include in the various sections above, I came across Sandi Clement's page on Magnetic Microbes listed for Bacteria that know where north is . Turns out that is part of a larger site with a theme rather similar to this one -- and written by students in a class on Extreme and Unusual Microbes taught by Dr. Rick Martin at the Center for Microbial Ecology, Michigan State Univ. The site is called The Curious Microbe - Essays of the Extreme and the Unusual : commtechlab.msu.edu/Sites/dlc...us/cindex.html.

• Robert Bruner ( http://bbruner.org )

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Vaccine breakthrough means no more chasing strains

Scientists at UC Riverside have demonstrated a new, RNA-based vaccine strategy that is effective against any strain of a virus and can be used safely even by babies or the immunocompromised.

Every year, researchers try to predict the four influenza strains that are most likely to be prevalent during the upcoming flu season. And every year, people line up to get their updated vaccine, hoping the researchers formulated the shot correctly.

The same is true of COVID vaccines, which have been reformulated to target sub-variants of the most prevalent strains circulating in the U.S.

This new strategy would eliminate the need to create all these different shots, because it targets a part of the viral genome that is common to all strains of a virus. The vaccine, how it works, and a demonstration of its efficacy in mice is described in a paper published today in the Proceedings of the National Academy of Sciences .

"What I want to emphasize about this vaccine strategy is that it is broad," said UCR virologist and paper author Rong Hai. "It is broadly applicable to any number of viruses, broadly effective against any variant of a virus, and safe for a broad spectrum of people. This could be the universal vaccine that we have been looking for."

Traditionally, vaccines contain either a dead or modified, live version of a virus. The body's immune system recognizes a protein in the virus and mounts an immune response. This response produces T-cells that attack the virus and stop it from spreading. It also produces "memory" B-cells that train your immune system to protect you from future attacks.

The new vaccine also uses a live, modified version of a virus. However, it does not rely on the vaccinated body having this traditional immune response or immune active proteins -- which is the reason it can be used by babies whose immune systems are underdeveloped, or people suffering from a disease that overtaxes their immune system. Instead, this relies on small, silencing RNA molecules.

"A host -- a person, a mouse, anyone infected -- will produce small interfering RNAs as an immune response to viral infection. These RNAi then knock down the virus," said Shouwei Ding, distinguished professor of microbiology at UCR, and lead paper author.

The reason viruses successfully cause disease is because they produce proteins that block a host's RNAi response. "If we make a mutant virus that cannot produce the protein to suppress our RNAi, we can weaken the virus. It can replicate to some level, but then loses the battle to the host RNAi response," Ding said. "A virus weakened in this way can be used as a vaccine for boosting our RNAi immune system."

When the researchers tested this strategy with a mouse virus called Nodamura, they did it with mutant mice lacking T and B cells. With one vaccine injection, they found the mice were protected from a lethal dose of the unmodified virus for at least 90 days. Note that some studies show nine mouse days are roughly equivalent to one human year.

There are few vaccines suitable for use in babies younger than six months old. However, even newborn mice produce small RNAi molecules, which is why the vaccine protected them as well. UC Riverside has now been issued a US patent on this RNAi vaccine technology.

In 2013, the same research team published a paper showing that flu infections also induce us to produce RNAi molecules. "That's why our next step is to use this same concept to generate a flu vaccine, so infants can be protected. If we are successful, they'll no longer have to depend on their mothers' antibodies," Ding said.

Their flu vaccine will also likely be delivered in the form of a spray, as many people have an aversion to needles. "Respiratory infections move through the nose, so a spray might be an easier delivery system," Hai said.

Additionally, the researchers say there is little chance of a virus mutating to avoid this vaccination strategy. "Viruses may mutate in regions not targeted by traditional vaccines. However, we are targeting their whole genome with thousands of small RNAs. They cannot escape this," Hai said.

Ultimately, the researchers believe they can 'cut and paste' this strategy to make a one-and-done vaccine for any number of viruses.

"There are several well-known human pathogens; dengue, SARS, COVID. They all have similar viral functions," Ding said. "This should be applicable to these viruses in an easy transfer of knowledge."

• Cold and Flu
• Infectious Diseases
• Immune System
• HIV and AIDS
• Flu vaccine
• Global spread of H5N1 in 2006
• Global spread of H5N1
• Acupuncture
• MMR vaccine

Story Source:

Materials provided by University of California - Riverside . Original written by Jules Bernstein. Note: Content may be edited for style and length.

Journal Reference :

• Gang Chen, Qingxia Han, Wan-Xiang Li, Rong Hai, Shou-Wei Ding. Live-attenuated virus vaccine defective in RNAi suppression induces rapid protection in neonatal and adult mice lacking mature B and T cells . Proceedings of the National Academy of Sciences , 2024; 121 (17) DOI: 10.1073/pnas.2321170121

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• v.8; Jan-Dec 2020

A Case Series of Patients Coinfected With Influenza and COVID-19

Venu madhav konala.

1 Ashland Bellefonte Cancer Center, Ashland, KY, USA

Sreedhar Adapa

2 Adventist Medical Center, Hanford, CA, USA

Srikanth Naramala

Avantika chenna.

3 Phoebe Putney Memorial Hospital, Albany, GA, USA

4 Medical College of Georgia, Augusta, GA, USA

Shristi Lamichhane

5 Interfaith Medical Center, Brooklyn, NY, USA

Pavani Reddy Garlapati

Mamtha balla.

6 University of Toledo, OH, USA

7 Promedica Toledo Hospital, Toledo, OH, USA

Vijay Gayam

Coronavirus disease 2019, also called COVID-19, is a global pandemic resulting in significant morbidity and mortality worldwide. In the United States, influenza infection occurs mainly during winter and several factors influence the burden of the disease, including circulating virus characteristics, vaccine effectiveness that season, and the duration of the season. We present a case series of 3 patients with coinfection of COVID-19 and influenza, with 2 of them treated successfully and discharged home. We reviewed the literature of patients coinfected with both viruses and discussed the characteristics, as well as treatment options.

Introduction

Coronavirus disease 2019, also called COVID-19, is a global pandemic resulting in significant morbidity and mortality. The cluster outbreak of cases of pneumonia from severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) was reported in December 2019 in Wuhan, China. 1 The COVID-19 has spread across the world at a fierce pace, and the United States has the highest number of infected patients, which led to the highest mortality in the world. 2

The influenza pandemic occurs in the winter, and the mode of transmission is the same as that of COVID-19. The most common clinical symptoms in influenza are fever, cough, shortness of breath, fatigue, headache, and myalgia, which are similar to COVID-19. 3 There have been only a few cases of coinfection from influenza and COVID-19 reported before. In this article, we describe 3 cases of coinfected cases of influenza and COVID-19 in the United States.

Case Series

A 57-year-old male presented to the emergency department with a complaint of on and off fever as well as dry cough going on for 2 weeks and worsening shortness of breath for 2 days. He initially had a dry cough, which later became productive with brownish sputum. The fever was associated with headaches, sore throat, and myalgia and did not subside with ibuprofen and paracetamol. He denied any recent sick contact or recent travel. The patient’s past medical history was significant for hypertension, diabetes mellitus, and myocardial infarction–automatic implantable cardioverter defibrillator (AICD) insertion. The patient denied any history of smoking, alcohol use, or illicit drug use.

On admission, the patient had a temperature of 101.3 °F, pulse rate of 123 beats per minute, respiratory rate of 22 breaths per minute, blood pressure of 100/90 mm Hg, and oxygen saturation of 92% on room air. Physical examination was significant for right basal crackles and palpable AICD.

The electrocardiogram showed sinus tachycardia without ST-T wave changes and normal QTc interval. Chest X-ray showed septal bilateral patchy lung infiltrates versus atelectasis ( Figure 1 ). The patient underwent computed tomography (CT) of the chest without contrast, which showed patchy bilateral ground-glass opacities in the periphery of both lungs ( Figure 2 ) with suspicion for COVID-19 given clinical symptoms and radiological findings.

Chest X-ray showing septal bilateral patchy lung infiltrates.

Computed tomography of the chest without contrast showing patchy bilateral ground-glass opacities in the periphery of both lungs.

The patient was admitted to the medical floor for treatment of pneumonia as well as to rule out COVID-19 infection. Influenza and COVID-19 nasopharyngeal swabs were sent. The patient was started on 3 L of oxygen via nasal cannula with oxygen saturations above 95%. He was started on antibiotics with ceftriaxone and azithromycin. The patient was positive for both COVID-19 and influenza A. The patient was then started on oseltamivir along with hydroxychloroquine with QTc monitoring after an infectious disease and pulmonary consult. The patient completed a 5-day course of ceftriaxone, azithromycin, hydroxychloroquine, and oseltamivir. The patient remained afebrile and was saturating above 95% on room air for 72 hours and was discharged home.

A 35-year-old female presented with fever, headaches, dry cough, worsening shortness of breath, and diarrhea for 5 days. The highest recorded fever at home was 104 °F, which responded to acetaminophen. The patient worked as an airline manager and has not traveled, but has come in contact with a large number of international travelers. Her past medical history was significant for sickle cell trait.

On admission, the patient’s temperature was 103.3 °F, pulse rate of 121 beats per minute, respiratory rate of 18 breaths per minute, blood pressure of 117/70 mm Hg, and oxygen saturation of 97% on room air. Physical examination was significant for tachycardia, respiratory distress, and fine crackles on the left lower chest on auscultation.

The electrocardiogram showed sinus tachycardia at a ventricular rate of 121 beats per minute without ST-T wave changes along with normal QTc intervals. A portable chest X-ray reported moderate bilateral alveolar infiltrates right more than left ( Figure 3 ). CT scan of the chest without contrast revealed extensive scattered bilateral infiltrates right greater than left ( Figure 4 ). Given the patient’s history as well as radiological findings, COVID-19 was suspected.

Chest X-ray showing moderate bilateral alveolar infiltrates right more than left.

Computed tomography of the chest without contrast showing extensive scattered bilateral infiltrates right greater than left.

The patient subsequently tested positive for influenza A and COVID-19. Blood and urine cultures revealed no growth. The patient was treated with intravenous (IV) ceftriaxone, IV azithromycin, and oseltamivir. She also received hydroxychloroquine after COVID-19 was positive. Corrected QTc interval was monitored regularly. After consecutive 6 days of fever, the patient remained afebrile from day 7 onward. Oxygen saturation was maintained with oxygen 2 to 3L via nasal cannula. The patient was discharged home after she reported symptomatic improvement in shortness of breath and fever.

A 68-year-old female presented to the emergency department with a chief complaint of altered mental status and worsening shortness of breath along with mild diarrhea. Detailed history could not be elicited because of altered mental status. Her past medical history was significant for diabetes mellitus, hypertension, and gastroesophageal reflux disease.

On arrival to the emergency department, the patient was saturating 62% on room air, which improved to 90% with oxygen via a nonrebreather mask. The patient was tachycardic and tachypneic on the presentation at 119 beats per minute and respiratory rate at 28 breaths per minute, respectively. Her temperature was 102 °F, blood pressure of 100/82 mm Hg. Physical examination was significant for a confused patient in acute distress with tachypnea and tachycardia along with bibasal crackles. The patient’s condition continued to deteriorate and required intubation and ventilation due to respiratory muscle fatigue.

A portable chest X-ray revealed mild-to-moderate pulmonary venous congestion, hazy airspace opacities bilaterally, which may represent diffuse pneumonia versus alveolar edema and very small bilateral pleural effusions ( Figure 5 ). CT of chest without contrast showed extensive scattered bilateral infiltrates ( Figure 6 ). Electrocardiogram revealed a ventricular rate of 112 beats per minute with a corrected QTc interval of 450 ms.

Chest X-ray showing mild-to-moderate pulmonary venous congestion, hazy airspace opacities bilaterally.

Computed tomography of the chest without contrast showing extensive scattered bilateral infiltrates.

The patient tested positive for COVID-19 and influenza A and was treated with ceftriaxone, azithromycin, hydroxychloroquine. The patient also had acute kidney injury with a history of chronic kidney disease and improved with IV hydration. The patient, unfortunately, had a cardiac arrest on day 1 of admission with unsuccessful cardiac resuscitation.

The laboratory testing for all patients are summarized in Table 1 . All patients had lymphopenia along with elevated C-reactive protein, erythrocyte sedimentation rate, creatinine kinase, fibrinogen, D-dimer, interleukin-6 levels, lactic acid, and lactate dehydrogenase.

Summary of Laboratory Abnormalities.

Abbreviations: WBC, white blood cells; ESR, erythrocyte sedimentation rate; BUN, blood urea nitrogen; HbA1c, hemoglobin A1c; IL, interleukin; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory distress syndrome coronavirus 2.

The novel coronavirus spike (S) protein attaches to the membrane-bound angiotensin-converting enzyme 2 (ACE 2) and cleaved by serine proteases to gain access into the human cell. 4 ACE 2 is widely distributed in the lungs, kidneys, gastrointestinal tract, oral, and nasal mucosa. COVID-19 causes activated T-cell response and increased pro-inflammatory cytokines levels. In severe cases, these increased levels can cause a cytokine storm and damages healthy tissue than the virus. 4 , 5

COVID-19 causes mostly fever, cough, sore throat, and shortness of breath, which in most cases are self-limiting. Some individuals harbor the virus and are asymptomatic. They play a crucial role in the spread of the virus in the community. 1

COVID-19 primarily affects the lungs causing dyspnea, hypoxia, and can cause severe infections resulting in acute respiratory distress syndrome (ARDS). In severe cases, patients often need intensive care unit admission causing multi-organ failure and death. 1

COVID-19 co-circulates in the environment along with other respiratory viruses and, most importantly, influenza. The study from a hospital in Wuhan, which analyzed the epidemiological, demographic, and laboratory data from the COVID-19 and influenza cases visited between January 2017 and February 2020. There was a decreased number of influenza A and B cases in 2020 compared with the previous years. COVID-19 interfered with the seasonal influenza epidemic. There were 9 coinfection cases of influenza and COVID-19 reported in 1054 cases. 6 As per Centers for Disease Control and Prevention estimates from 2018-2019, approximately 35 million people were infected with influenza that resulted in approximately half million hospitalizations. Thirty-four thousand patients died from influenza last year. 3

A double-center study was done in China to analyze coinfections of common respiratory pathogens in COVID-19. A total of 68 patients with SARS-CoV-2 infection were recruited, 38 from Wuhan and 30 from Quingdao. Among them, 24 (80%) patients from Quingdao had an immunoglobulin M antibody against 1 respiratory pathogen, compared with only 1 patient in Wuhan. The most common respiratory pathogens detected were influenza A, influenza B in the majority of cases, followed by Mycoplasma pneumonia and Legionella pneumophilia . This shows that the coinfection pattern differs significantly depending on the geographic area. 7

In an experience described by Wuhan, only 5 patients among 115 were coinfected with influenza and COVID-19. In those 5 patients, 3 patients had influenza A, and 2 patients had influenza B. All the patients had a fever, cough, and shortness of breath. Two patients developed fatigue, myalgia, headache, and expectoration. Three patients had pharyngalgia, which appeared more in the patients who developed coinfection. Only 1 patient developed chest pain and hemoptysis. The laboratory data revealed lymphocytopenia and elevated C-reactive protein in 4 patients, elevated transaminases, and procalcitonin levels in 2 patients. Lymphocyte count improved during the remission of the disease. The renal function and coagulation function was normal in these patients. Only 1 patient among the 5 patients developed ARDS and needed noninvasive-assisted ventilation and improved. The chest CT of the patient who developed ARDS had significant ground-glass opacities and subsegmental areas of consolidation that correlated with the clinical picture. Acute liver injury was noted in 3 patients and diarrhea in 2 patients. All patients were treated with antiviral therapy, including oseltamivir, antibiotic therapy, and received supplemental oxygen. Three patients were treated with glucocorticoids. No one needed care in intensive care unit, and all the patients were discharged home. 8

Wu et al reported a case of a 69-year-old male who presented with fever and dry cough after visiting Wuhan during the time of the COVID-19 outbreak. The patient’s CT revealed ground-glass consolidation in the right lung inferior lobes. COVID-19 was suspected, nasopharyngeal swab specimen resulted negative for SARS-CoV-2 on repeated testing, but yielded positive for influenza A. The patient was discharged on oral oseltamivir and was instructed to remain in isolation at home. Subsequently, in a week, the patient developed ARDS and lymphopenia. Repeated testing by nasopharyngeal swab and sputum sample was negative. The patient was subsequently intubated, and finally, bronchoalveolar lavage fluid was tested positive for SARS-CoV-2. This case highlights that both influenza and SARS-CoV-2 mimic the clinical picture, and often the diagnosis of COVID-19 can be missed with false-negative tests for the upper respiratory specimen. If the suspicion for COVID-19 is high, repeated testing should be performed. 9

Four cases of coinfection with SARS-CoV-2 and influenza were reported from Iran. Three of the patients were males, relatively younger, except for 1 patient, and only 1 patient has comorbidities. All the patients had a cough, dyspnea, and fever, while the majority had headache and myalgia. One patient had gastrointestinal symptoms. The majority had lymphopenia and elevated inflammatory markers. All the patients had radiological abnormalities. Significant renal failure was noted in 1 patient, and liver failure was noted in 2 patients. No outcomes were described in the patients. 10

There is no proven therapy for COVID-19 till now; meticulous supportive care holds key. The patients are getting treated with hydroxychloroquine, azithromycin, as seen in our case series and in severe cases, interleukin-6 antibodies. Novel nucleoside analog-like remdesivir was also used. The treatment with steroids is controversial. There have been many emerging and experimental therapies described. Many clinical trials are underway across the globe to check the efficacy of different medications in COVID-19. In a few centers, the convalescent serum has been used. Patients with influenza should be treated with oseltamivir. Multiple clinical trials are under investigation as summarized in Table 2 . 11

Multiple Treatment Options Under Investigation for COVID-19.

Abbreviations: IV, intravenous; SARS-CoV-2, severe acute respiratory distress syndrome coronavirus 2; NA, not applicable; SOC, standard of care; BCG, Bacillus Calmette-Guérin.

Influenza and SARS-CoV-2 cause mostly similar symptoms, and the coinfection did not significantly worsen the symptoms or outcomes.

Influenza and SARS-CoV-2 coinfection can occur in patients with similar symptoms. The coinfection did not significantly worsen the symptoms and outcomes. It is essential to recognize coinfections as the treatment can be completely different. Patients should get vaccinations for common respiratory pathogens if available, to reduce the risk of coinfection.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.

Informed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article. For patient 3, consent was obtained from next of kin.