mBio: Coronavirus Has An Affinity For Multiple Hosts

 

Photo Credit NIAID

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Most of the infectious diseases that afflict mankind today began in a different animal species, but jumped to humans and then adapted to our physiology.  

 

• The scourge of Tuberculosis, which now infects 1/3rd of humanity, likely jumped species when man began to corral and raise its traditional hosts; goats and cattle.
• Measles appears to have evolved from canine distemper and/or the Rinderpest virus of cattle.  
• Influenza, as most of you know, is native to aquatic birds – but jumped species thousands of years ago and many strains have adapted to humans, pigs, and other species.

 

The list of zoonotic diseases (those shared between humans and animals) is long and continually expanding, and includes: SARS, Babesiosis, Borrelia (Lyme), Nipah, Hendra, Malaria, Hantavirus, Ebola, Bartonella, Leptospirosis, Q-Fever, bird flu and many, many others

 

Most viruses are fairly selective about the type of cells they will invade, what organ systems they will attack, and even what species they will infect.

 

Horse viruses generally attack equines, and not say, cats and dogs.   Cat viruses tend to attack felines, and not birds.  Bird viruses usually only infect avian species.

 

But some viruses are more promiscuous than others.

Rabies can infect nearly all warm-blooded animals, and we’ve seen the H5N1 `avian flu’ virus infect a wide range of mammals, including humans, dogs, cats, and pigs.

 

Later today, mBio®, the online open-access journal of the American Society for Microbiology, will publish a study that looks at the host range of the newly discovered coronavirus (hCoV-EMC) in the Middle East.

Although researchers are still looking for the receptor cell that allows entry of the virus into the host’s cells, they have found that the hCoV-EMC virus can infect a number of bat species, along with pigs, and of course, humans.

 

We’ll have to wait a few hours to see the study, but the ASM has a press release with some of the details, and we also have an excellent write up by Helen Branswell of the Canadian Press.

 

First, excerpts from the press Release

Public release date: 11-Dec-2012

New coronavirus has many potential hosts, could pass from animals to humans repeatedly

The SARS epidemic of 2002-2003 was short-lived, but a novel type of human coronavirus that is alarming public health authorities can infect cells from humans and bats alike, a fact that could make the animals a continuing source of infection, according to a study to be published in in mBio®, the online open-access journal of the American Society for Microbiology, on December 11. The new coronavirus, called hCoV-EMC, is blamed for five deaths and several other cases of severe disease originating in countries in the Middle East.

 

According to the new results, hCoV-EMC uses a different receptor in the human body than the SARS virus, and can infect cells from a wide range of bat species and pigs, indicating there may be little to keep the virus from passing from animals to humans over and over again.

 

First identified in a patient in Saudi Arabia in June, nine laboratory-confirmed cases of hCoV-EMC infection have now been identified, five of whom have died. Although the virus does not apparently pass from person-to-person very readily, the case fatality rate and the fact that the source of the virus has not been identified have caused concern among global public health authorities. Cases of hCoV-EMC infection are marked by severe pneumonia and often by kidney failure.

 

"This virus is closely related to the SARS virus, and looking at the clinical picture, it causes the same pattern of disease," says Christian Drosten of the University of Bonn Medical Centre in German, a lead author of the study.

 

Given the similarities, Drosten and his colleagues wanted to know whether hCoV-EMC and SARS might use the same receptor, a sort of molecular "dock" on human cells that the virus latches onto to gain entry to the cell. The SARS receptor, called ACE2, is found mostly on pneumocytes deep within the human lung, so an individual must breathe in many, many SARS viruses for a sufficient number of them to reach this susceptible area and cause an infection. Drosten says this simple fact helped ensure the SARS outbreak didn't spread like wildfire and was mostly limited to healthcare workers and residents of overcrowded housing in Hong Kong. Also, once a person was infected with SARS in the deep part of their lungs, he or she felt sick almost immediately and therefore was not active in the community and infecting others, another aspect of the receptor that helped curb the outbreak.

 

Does hCoV-EMC use the same receptor? If so, the means of controlling this new virus might become clearer.

 

"The answer is a clear no," says Drosten. "This virus does not use ACE2." This leaves open the possiblity that hCoV-EMC could use a receptor in the human lung that is easier to access and could make the virus more infectious than SARS, but it is still not known what receptor the virus does use.

 

To help identify how hCoV-EMC might have originated and moved between humans and animals, the second part of the study focused on the animal species the virus can infect. SARS is closely related to viruses from bats, but Drosten says the virus changed in the transition from bats to civet cats to humans and could no longer infect bats, so SARS was not present in the wild and did not pass repeatedly from bats to humans like a classical zoonotic disease. "So the [SARS] virus lost its old host and gained a new one," says Drosten.

 

Like SARS, hCoV-EMC is most closely related to coronaviruses from bats, but unlike SARS, this study found that hCoV-EMC can still infect cells from many different species of bats. "This was a big surprise," says Drosten. "It's completely unusual for any coronavirus to be able to do that – to go back to its original reservoir." The virus is also able to infect cells from pigs, indicating that it uses a receptor structure that all these animals have in common. If that receptor is present in mucosal surfaces, like the lining of the lung, it is possible the virus could pass from animals to humans and back again, making animals an ongoing source of the virus that would be difficult or impossible to eliminate.

(Continue . . . )

 

The study should be published online at http://mbio.asm.org/ later today.

 

Meanwhile, Helen Branswell has the following report.

 

Study finds puzzling behaviour of new coronavirus, may hint at pattern of spread

By Helen Branswell, The Canadian Press | Associated Press – 7 hrs ago

TORONTO - A new study reveals that the new SARS-like virus which has been causing infections in the Middle East behaves unusually in laboratory testing

(Continue . . . )

»» Read More

mBio: Should The H5N1 Research Moratorium End?

 

BSL-4 Lab Worker - Photo Credit –USAMRIID  

 

 

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Ten months ago, during the prolonged debate over the publication of a pair of controversial research papers (see The Furor Over H5N1 Research Continues), a group of the world’s leading researchers announced a 60 day moratorium on specific types of bird flu research (see Scientists Announce 60 Day Moratorium On Some H5N1 Research).

 

While the research papers by Fouchier and Kawaoka on the genetic changes needed to provide H5N1 with enhanced transmissibility have now been published, the self-imposed moratorium remains in place.

 

Scientists, biosecurity experts, and policy makers continue to struggle with how to proceed with H5N1 research that potentially falls under the category of DURC -  Dual Use Research of Concern.

 

For those unfamiliar with the lexicon of biomedical research, DURC is defined as:

 

. . . life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security.

 

Last March the Office of Science Policy at the NIH released a 4 page set of guidelines for DURC projects, and ordered a review of all current life sciences projects (U.S. Issues New DURC Oversight Rules).

 

Later today the journal mBio will publish a series of opinion pieces regarding H5N1 research by some of the most influential researchers in influenza virology and biosecurity.

We’ve got a preview from a press release, which ought to whet or appetites until the new issue goes live later today (LINK).    Some excerpts follow:

 

202-942-9297
American Society for Microbiology

Research on enhanced transmissibility in H5N1 influenza: Should the moratorium end?

How can scientists safely conduct avian flu research if the results could potentially threaten, as well as save, millions of lives? In a series of commentaries appearing on Tuesday, October 9 in mBio®, the online open-access journal of the American Society for Microbiology, prominent microbiologists and physicians argue the cases both for and against lifting a voluntary moratorium on experiments to enhance the ability of the H5N1 virus to move from mammal to mammal, so-called "gain-of-function" research, and discuss the level of biosecurity that would be appropriate for moving that research forward.

 

<SNIP>

 

Enhancing and analyzing the transmissibility of the H5N1 virus could, on the one hand, provide insights that could help prevent or treat a future outbreak of H5N1 , or, on the other hand, it may provide a roadmap for a "bad actor" to deliberately bring about an influenza pandemic or lead to an inadvertent release of a virus with enhanced transmissibility.

Authors of the commentaries are prominent scientists, including:

• Ron Fouchier of Erasmus MC Rotterdam in The Netherlands, Adolfo García-Sastre of the Mount Sinai School of Medicine, and Yoshihiro Kawaoka of the University of Wisconsin-Madison, lead authors of the two papers that began the controversy, argue that in the eight months since the moratorium was agreed upon, the international research community has had sufficient time to review biosafety and biosecurity measures and that H5N1 transmission studies ought to proceed.
• Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases contributes his voice as a representative of an organization that is a key funder of influenza research. Although Fauci acknowledges that the benefits of gain-of-function research outweigh the risks, he argues that scientists have yet to fully meet their responsibility for engaging the public in weighing these matters and making the case for proceeding. He outlines how the U.S. government plans to augment policy guidelines related to "dual use research of concern" like the experiments on enhanced influenza transmission.
• Marc Lipsitch and Barry R. Bloom of the Harvard School of Public Health explain why they view H5N1 with enhanced transmissibility as a "potential pandemic pathogen," representing an even greater threat to global health than Ebola and other biosafety level 4 (BSL-4) pathogens. They argue that research on enhanced H5N1 and other potential pandemic pathogens requires a new, more stringent set of guidelines for safety, thorough public discussion of the risks and benefits involved, and global guidelines for laboratory procedures, among other measures to minimize the risk of laboratory-released infections or epidemics.
• Ian Lipkin of Columbia University argues that once research on enhanced strains of H5N1 continues it may be advisable to conduct the work only in BSL-3 Ag laboratories that meet additional, enhanced guidelines for handling agents with pandemic potential. Lipkin proposes that any course should be charted in consultation with and oversight from the global scientific and regulatory community.
• Stanley Falkow of Stanford University provides perspective on the H5N1 research moratorium based on his own experiences with a similar situation in the 1970s, when research in recombinant DNA techniques was halted while a committee of scientists and non-scientists could establish a set of guidelines for conducting the work safely. Falkow argues that research on H5N1 viruses with enhanced transmissibility should move forward once scientists work with the public to establish standardized guidelines using common sense and scientific creativity.

(Continue . . . )

 

While the papers of Fouchier and Kawaoka sparked this vigorous (and at times heated) debate over the risks of creating a better bird flu virus, many of the same issues apply to other areas of biological research.

 

Among them:

• How are we to handle this brave new world of life sciences, where new viruses and other life forms can be created in the laboratory?
• Who is to decide on what is appropriate, or safe research?
• Who decides what should be published, and who should have access to redacted information?
• What laboratory protocols and protections are necessary for working the the H5N1 virus, and other virulent pathogens?

 

We are entering a new era of scientific discovery, one where great things are possible. But those advances will be for naught if the public loses faith in the science, or the scientists.

 

You can create a genetically modified dengue-resistant mosquito, but if the public fears it more than the disease, all you have is an expensive laboratory curiosity.

 

And a universal flu vaccine – one that could forever stave off the global threat of influenza pandemics -only works if it is accepted by the vast majority of the public as being safe, effective, and necessary.

 

As I wrote in Science At The Crossroads, the public’s faith in science and technology is teetering. 

 

According to a UK poll (Public Attitudes To Science, May 2011), while the majority of respondents (79%) believe science has, on the whole, made our lives easier . . .  astonishingly, just 54% believe that the benefits of science are greater than any harmful effect.

 

One only has to look at the deep divisions over climate change, evolution, vaccine safety, nuclear power, and genetically modified food crops to realize just how wide this rift between the public, and scientists, has become.

 

Which makes getting policy on H5N1 research (and other DURC projects) right, and as safe as possible, absolutely imperative.

 

Given the public’s sentiment, the burgeoning field of Life Sciences (which includes bio-engineering) can ill afford a misstep if they hope to gain and hold the public’s acceptance.

»» Read More

mBio: Taubenberger et al. On the 1918 Spanish Flu

Credit CDC PHIL

 

 

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mBio, the American Society for Microbiology’s online, open access journal, has published a long and fascinating review this morning on what we’ve learned over the past 15 years about the 1918 H1N1 `Spanish Flu’ pandemic virus, written by some of the biggest experts in the field.

 

At this point, I’ll just step aside and invite you to read:

 

 

Reconstruction of the 1918 Influenza Virus: Unexpected Rewards from the Past

 

Jeffery K. Taubenberger, David Baltimore, Peter C. Doherty, Howard Markel, David M. Morens, Robert G. Webster and Ian A. Wilson

 

doi:10.1128/mBio.00201-12

 

Highly recommended.

»» Read More

mBio: A Mammalian Adapted H3N8 In Seals

Photo Credit Wikipedia

 

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Even though the actual study has not appeared online (now online) in the journal mBio, overnight we’ve seen more than a half dozen stories on soon-to-be published research into a novel influenza virus that infected and killed more than 160 seals along the New England coast last year.

 

You’ll find an excellent report from Carl Zimmer in the New York Times (see Flu That Leapt From Birds to Seals Is Studied for Human Threat), as well as this reportage from the BBC (see New flu virus found in seals concerns scientists)

 

Regular readers may recall this story from last fall (see New England Seal Deaths Tied to H3N8 Flu Virus & NOAA: New England Dead Seals Test Positive For Flu), but in brief:

 

In early October of 2011 media reports indicated that scores of dead seals had been discovered along the shoreline of New England, predominantly from the North Shore of Massachusetts to the southern coast of Maine.

 

In November NOAA declared these deaths an “Unusual Mortality Event”, cautioned the public to avoid contact with seals, and directed more resources to study the event.

 

Although the cause of these deaths was still undetermined, some researchers saw similarities to a seal die off that had occurred 30 years earlier.

 

In that instance, the culprit turned out to be an H7N7 influenza. (see Isolation of an influenza A virus from seals G. Lang, A. Gagnon and J. R. Geraci)

 

In December it was announced that the pathogen behind this latest seal die off was a variant of the H3N8 avian flu strain, versions of which are known to also infect horses and dogs.

 

Science team identifies influenza virus subtype that infected five dead seals

Risk to humans and pets low; tests continue

 

Harbor Seals (Credit NOAA)

A virus similar to one found in birds but never before in harbor seals was the cause of five of 162 recent deaths of the animals  in New England, according to a group of federal agencies and private partners.

 

This Influenza A virus subtype, H3N8, appears to have a low risk of transmission to humans. Experts continue to analyze this virus, and any findings of public health significance will be immediately released. The virus is not the infamous H5N1  virus that caused a global pandemic in 2007, or the H1N1 virus from 2009.

(Continue . . . )

 

While we tend to think of humans, pigs, and birds as the main hosts of influenza (and to a lesser extent dogs and horses), a number of other species are susceptible to some kinds of influenza strains as well.

 

• In That Touch Of Mink Flu I wrote about 11 farms in Holstebro, Denmark that were reported to be infected with a variant of the human H3N2 virus back in 2009.
• The AVMA Pandemic Flu page documents species – including dogs, cats, turkeys, skunks, ferrets – that tested positive for the 2009 H1N1 pandemic virus.
• While less commonly reported - camels, whales and seals have all been shown to be susceptible to influenza (cite Evolution and ecology of influenza A viruses R.G. Webster et al.)

 

 

Fast forward eight months and today research is being published to show that the H3N8 virus collected from dead seals last fall has mutated from its avian origins to become better adapted to mammalian hosts. 

 

First stop, excerpts from a press release from the American Society for Microbiology, publishers of mBio.

 

 

New influenza virus from seals highlights the risks of pandemic flu from animals

A new strain of influenza virus found in harbor seals could represent a threat to wildlife and human health, according to the authors of a study appearing July 31 in mBio®, the online open-access journal of the American Society for Microbiology. It is crucial to monitor viruses like this one, which originated in birds and adapted to infect mammals, the authors say, so that scientists can better predict the emergence of new strains of influenza and prevent pandemics in the future.

 

"There is a concern that we have a new mammalian-transmissible virus to which humans haven't been exposed yet. It's a combination we haven't seen in disease before," says Anne Moscona of Weill Cornell Medical College in New York City, the editor of the report.

 

<SNIP>

 

The mBio® study analyzed the DNA of a virus associated with a die-off of 162 New England harbor seals in 2011. Autopsies of five of the seals revealed they apparently died from infection with a type of influenza called H3N8, which is closely related to a flu strain that has been circulating in North American birds since 2002. Unlike the strain in birds, this virus has adaptations to living in mammals and has mutations that are known to make flu viruses more transmissible and cause more severe disease. The virus also has the ability to target a receptor called SAα-2,6, a protein found in the human respiratory tract.

(Continue . . . )

Another press release, from Columbia University's Mailman School of Public Health, titled An avian flu that jumps from birds to mammals is killing New England's baby seals cautions:

 

Based on full genome sequencing and phylogenetic analysis, seal H3N8 descended from an avian strain that has been circulating in North American waterfowl since 2002, which implies recent transmission from wild birds to seals.

 

Accordingly, seal H3N8 has acquired the ability to bind sialic acid receptors that are commonly found in the mammalian respiratory tract. Mutations in the HA and PB2 genes – required for cell entry and replication, respectively – suggest enhanced virulence and transmission in mammals, but these putative attributes require further investigation. Given these findings along with the long history of the spread of avian influenza to humans—most notably H1N1 and H5N1—seal H3N8 could pose a threat to public health.

 

 

Regular readers of this blog are aware that avian influenza strains bind preferentially to the kind of receptor cells commonly found in the digestive and respiratory tracts of birds; alpha 2,3 receptor cells.

 

Human (and mammalian adapted) influenzas – on the other hand - bind to the kind of receptor cells that line the surfaces of the human upper respiratory system; alpha 2,6 receptor cells.

 

 

In both the BBC and NYTs report, one of the authors of this study – celebrated virus hunter Professor Ian Lipkin of Columbia University – expressed concerns over the discovery that seals – like pigs – have both types of receptor cells.

 

If infected by two different strains simultaneously, they could act as a `mixing vessel’ for influenza strains, and produce a hybrid (reassorted) virus. 

 

 

Every day, it seems, we learn more about how remarkably well these influenza viruses evolve and adapt. Despite decades of work by thousands of researchers, there is still so very much we are just beginning to understand.

 

Although the public health threat from H3N8 is hard to quantify, this is yet another example of how Nature’s laboratory is open and operating 24/7, and why we need to remain alert and prepared for the next pandemic threat that may emerge.

 

When the mBio study is published, I’ll post the link here.

 

NOW ONLINE:

 

Emergence of Fatal Avian Influenza in New England Harbor Seals

S. J. Anthony, J. A. St. Leger, K. Pugliares, H. S. Ip, J. M. Chan, Z. W. Carpenter, I. Navarrete-Macias, M. Sanchez-Leon, J. T. Saliki, J. Pedersen, W. Karesh, P. Daszak, R. Rabadan, T. Rowles and W. I. Lipkin

doi:10.1128/mBio.00166-12

»» Read More

mBio: The H5N1 Biosafety Level Debate

 

UPDATED: mBio has published4 editorial/commentary pieces on the H5N1 research debate.  I’ve posted the links at the bottom of this blog post.

 

 

 

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Later today mBio will publish a pair of opposing views on what level of  laboratory biosecurity (BSL-3 or BSL-4) should be required in order to work on the H5N1 virus.

 

While there are many differences in procedures between them, in the broadest definition under BSL-3 it is the pathogen that is kept isolated, and worked on in specially designed negative airflow biological safety cabinets (BSC). Lab personnel wear fairly standard PPEs (Personal Protective Equipment) in BSL-3 labs.

 

With enhanced BSL-4 security, the focus is on isolating and protecting lab workers from the pathogen, and so they must all wear fully contained BSL-4 `space suits’, and decontaminate before leaving the work area.

 

BSL-4 labs work on the most dangerous pathogens that pose a particularly high risk of infection, such as Marburg, Ebola, Lassa fever, CCHF, and smallpox.

 

BSL-4 labs are far more expensive to build and maintain than BSL-3 facilities, and there are not nearly as many of them around the world.

 

Which presents a dilemma.  If you restrict work on the H5N1 virus to only BSL-4 labs, that would exclude many universities (and even entire countries) from being able to conduct research on the virus.

 

You may recall that early in February Canada restricted H5N1 research to BSL-4 facilities (see  Canada Issues Biosafety Advisory For H5N1 Research).

 

Although the mBio articles won’t be published for a few more hours, we’ve got a press release with some of the details and a preview by Helen Branswell.

First stop, the press release from the American Society for Microbiology

 

New H5N1 viruses: How to balance risk of escape with benefits of research?

In the controversy surrounding the newly developed strains of avian H5N1 flu viruses, scientists and policy makers are struggling with one question in particular: what level of biosafety is best for studying these potentially lethal strains of influenza? In a pair of commentaries, researchers from the Mount Sinai School of Medicine in New York and the University of Michigan argue their different views of how to safely handle H5N1 flu viruses. The commentaries will be published in mBio®, the online open-access journal of the American Society for Microbiology, on Tuesday, March 6.

 

This fall, the U.S. National Science Advisory Board for Biosecurity (NSABB) set off a debate when it asked the authors of two recent H5N1 research studies and the scientific journals that planned to publish them to withhold crucial details of the research in the interest of biosecurity. The researchers had taken H5N1, a virus that cannot easily transmit from human to human, and developed strains of the virus that can transmit easily between ferrets, which are a common model for human influenza.

 

These H5N1 strains and others like them that might be developed in the future could pose a grave threat to human life, but researchers and others argue that studying these H5N1 strains could help bolster preparedness efforts and vaccine development to help fend off a potential H5N1 pandemic. How can we balance the need to protect human life from the accidental escape of an H5N1 strain with the need to continue research that might prevent a naturally occurring outbreak? Which biosafety level (BSL) is right for the H5N1 virus?

 

In the commentaries appearing in mBio, two experts offer opposing views of the appropriate level of security for dealing with H5N1 viruses. The authors agree that, with a reported case fatality rate that could be as high as 50% or more, H5N1 could create a pandemic of disastrous proportions, but they differ in their opinions of how to strike a balance between biosecurity and potentially life-saving research.

(Continue . . . )

 

Next up, from the Canadian Press, a preview from Helen Branswell.

 

The Canadian Press - ONLINE EDITION

Future work on lab-made bird flu viruses should be done in most secure labs

By: Helen Branswell, The Canadian Press

Posted: 03/6/2012 3:02 AM TORONTO - Future work on mutated bird flu viruses should only take place in laboratories with the highest level of biosafety, suggests a new commentary on the controversy over two studies that led to the creation of these viruses.

 

But an opposing view argues that to restrict work on the viruses to so-called BSL4 labs would not leave the world safer, but would impede the quest to find out how flu viruses that normally infect birds can adapt to infect people.

(Continue . . .)

 

Both opinion pieces should be online at 10am EST, March 6th, and available at this link.

 

Mammalian-Transmissible H5N1 Virus: Containment Level and Case Fatality Ratio

Arturo Casadevall and Thomas Shenk

doi:10.1128/mBio.00054-12

 

Working Safely with H5N1 Viruses

Adolfo García-Sastre

doi:10.1128/mBio.00049-12

 

Biosafety Considerations of Mammalian-Transmissible H5N1 Influenza

Michael J. Imperiale and Michael G. Hanna III

doi:10.1128/mBio.00043-12

 

Ferret-Transmissible Influenza A(H5N1) Virus: Let Us Err on the Side of Caution

Lisa N. Murillo

doi:10.1128/mBio.00037-12

»» Read More

mBio: Lethal Synergism of H1N1 Pandemic Influenza & Bacterial Pneumonia

 

 

 

CDC PHIL - Photomicrograph of Streptococcus (Diplococcus) pneumoniae bacteria

 

# 5856

 

 

While the vast majority of people who contracted the H1N1 pandemic flu of 2009 recovered without incident, a very small minority saw severe – sometimes fatal – illness. 

 

Often during 2009 we saw reports of severe lung damage. Damage that in some cases was compared to what has been seen in H5N1 bird flu and during the great pandemic of pandemic of 1918.

 

A few of the stories from back then include:

 

In early September of 2009, in Pathology Of Fatal H1N1 Lung Infections, we looked at a report by Helen Branswell that looked early autopsy results.

 

 

Lung damage in fatal swine flu cases more bird flu than seasonal flu: expert

By Helen Branswell Medical Reporter (CP) 

TORONTO — The lungs of people who have died from swine flu look more like those of the victims of H5N1 avian influenza than those of people who succumb to regular flu, the chief of infectious diseases pathology at the U.S. Centers for Disease Control says.

 

Study of about 70 fatal H1N1 cases so far also reveals there may be more incidences of co-infections with bacteria than was earlier thought, Dr. Sherif Zaki told The Canadian Press in an interview.

 

A couple of weeks later in More On The Pathology Of Novel H1N1, we saw a report by Maggie Fox, then Health and Science Editor for Reuters, who brought us more details of this  story, including comments by Dr. Sherif Zaki of the U.S. CDC who  stated that "This is almost exactly what we see with avian flu. This looks like avian flu on steroids."

 

That same month, I wrote about the use of ECMO (Extracorporeal Membrane Oxygenation) in the treatment of severe lung injury in H1N1 victims in The ECMO Option.

 

In early December (see NIH: Post Mortem Studies Of H1N1) the NIH announced the results of a series of autopsies conducted on H1N1 victims in New York City over the summer, which are chronicled in the Archives of Pathology & Laboratory Medicine.

 

The NIH put together a press release, which provided highlights of the study.

 

FOR IMMEDIATE RELEASE
Monday, Dec. 7, 2009

Media Contact: Anne A. Oplinger
(301) 402-1663
niaidnews@niaid.nih.gov

New York Autopsies Show 2009 H1N1 Influenza Virus Damages Entire Airway

In fatal cases of 2009 H1N1 influenza, the virus can damage cells throughout the respiratory airway, much like the viruses that caused the 1918 and 1957 influenza pandemics, report researchers from the National Institutes of Health (NIH) and the New York City Office of Chief Medical Examiner. The scientists reviewed autopsy reports, hospital records and other clinical data from 34 people who died of 2009 H1N1 influenza infection between May 15 and July 9, 2009. All but two of the deaths occurred in New York City. A microscopic examination of tissues throughout the airways revealed that the virus caused damage primarily to the upper airway—the trachea and bronchial tubes—but tissue damage in the lower airway, including deep in the lungs, was present as well. Evidence of secondary bacterial infection was seen in more than half of the victims.

 

The team was led by James R. Gill, M.D., of the New York City Office of Chief Medical Examiner and New York University School of Medicine, and Jeffery K. Taubenberger, M.D., Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID) at NIH. The findings are reported in the Archives of Pathology & Laboratory Medicine, now available online and scheduled to appear in the February 2010 print issue.

<SNIP>

“This pattern of pathology in the airway tissues is similar to that reported in autopsy findings of victims of both the 1918 and 1957 influenza pandemics,” notes Dr. Taubenberger.

 

While many people continued to insist that swine flu was no worse than seasonal flu, obviously something was different in the way it produced severe lung damage.  

 

A year into the pandemic, I summarized many of the ways that the 2009 H1N1 virus differed from seasonal flu in There’s No Flu Like A New Flu.

 

While the overall incidence of these complications was relatively low, those who suffered from them often experienced extremely severe illness.

 

 

All of which serves as prelude to an open access study, published today in mBio, called:

 

Lethal Synergism of 2009 Pandemic H1N1 Influenza Virus and Streptococcus pneumoniae Coinfection Is Associated with Loss of Murine Lung Repair Responses

John C. Kash^a, Kathie-Anne Walters^b, A. Sally Davis^a, Aline Sandouk^a, Louis M. Schwartzman^a, Brett W. Jagger^a, Daniel S. Chertow^a, Qi Li^a, Rolf E. Kuestner^b, Adrian Ozinsky^b, and Jeffery K. Taubenberger^a

 

 

The entire study is available, and is well worth reading, but briefly:

 

Scientists at NIAID and the Institute for Systems Biology (ISB) infected experimental mice with both seasonal flu and the 2009 H1N1 pandemic flu, and after 48 hours exposed some of them to Streptococcus pneumoniae, one of the main causes of pneumonia.

 

Mice that were exposed only to the two flu strains showed expected flu symptoms, but all survived.

Mice that were exposed to seasonal flu and S. pneumoniae experienced minor lung damage, but once again, all survived.

 

But all of the mice infected with the pandemic H1N1 virus, and S. pneumoniae showed severe weight loss, lung damage, and 100% mortality

 

Excerpts from the press release below explain what else they found:

 

American Society for Microbiology

 

2009 H1N1 pandemic flu more damaging to lungs, opens opportunities for bacterial infection

(EXCERPT)

The lung tissues of the dead mice revealed that the alveoli were severely inflamed and the surfaces of the bronchioles were wiped clean of the protective layer of cells called the epithelium. There was also increased bacterial replication in the lungs of the co-infected mice, a sign that the bacteria were thriving there.

 

Looking at the mouse genes that were expressed during infection revealed more details about how the pandemic influenza virus sets the stage for lethal bacterial infections. Mice infected with the pandemic flu virus and S. pneumoniae had a similar inflammatory response as the other mice, but they lack responses that would repair and regenerate their damaged epithelial cells, those protective tissues that would otherwise keep bacteria from penetrating to deeper layers of tissue.

 

All these factors add up to big problems in the lung: as compared with seasonal flu, infection with the pandemic strain of flu was associated with more extensive damage to the epithelium that requires more extensive tissue repair. This opens the body up to attack from bacterial invaders, including Streptococcus pneumoniae.

(Continue . . . )

 

So not only did this duel infection lead to greater lung damage, and increased bacterial replication, it also disabled the lung’s ability to repair itself.

 

Since it can take 6 months or longer to develop a vaccine for a novel influenza virus, these results may suggest a bigger role for the 23-valent Pneumonia vaccine (PPVSV) during a future pandemic. 

 

More than a year after the end of the 2009 pandemic, scientists are still uncovering basic information about how pandemic flu differs from seasonal flu. 

 

With luck, work like this will provide better ways for us to deal with an outbreak, when the next one arrives.

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mBio: A/H1N1 Potential For Mutation

 

# 5061

 

 

During the 18 months since it first emerged, the novel A/H1N1/2009 virus has remained remarkably stable.  Yet there remain ongoing concerns that the (former) pandemic virus might morph into a more virulent strain.

 

While we have seen sporadic oseltamivir resistance crop up, and a small percentage of samples have demonstrated small genetic changes (see Eurosurveillance: More On H1N1 Mutations), the evidence is inconclusive as to whether (or how much) any of these mutations actually affect the virulence or transmissibility of the virus.

 

 

This morning we’ve an open access article with an impressive pedigree (including Robert Webster/Richard Webby) from mBio - the online journal of the American Society for Microbiology – that looks at the potential for the pdmH1N1 virus to mutate or reassort with another virus, and produce a more virulent progeny.

I’ve reproduced the abstract below, the full text of the study can be accessed HERE. 

 

Fair warning: Parts of this study are fairly technical, and may be tough sledding for those not well versed in virology.

 

Go ahead and read the (slightly reformatted) abstract below or proceed to the full text. 

 

I’ll return with more after the break.

 

 

 

Does Pandemic A/H1N1 Virus Have the Potential To Become More Pathogenic?

1. Natalia A. Ilyushina, Mariette F. Ducatez, Jerold E. Rehg, Bindumadhav M. Marathe, Henju Marjuki, Nicolai V. Bovin, Robert G. Webster, and Richard J. Webby

ABSTRACT

Epidemiologic observations that have been made in the context of the current pandemic influenza virus include a stable virulence phenotype and a lack of propensity to reassort with seasonal strains.

 

In an attempt to determine whether either of these observations could change in the future, we coinfected differentiated human airway cells with seasonal oseltamivir-resistant A/New Jersey/15/07 and pandemic A/Tennessee/1-560/09 (H1N1) viruses in three ratios (10:90, 50:50, and 90:10) and examined the resulting progeny viruses after 10 sequential passages.

 

When the pandemic virus was initially present at multiplicities of infection equal to or greater than those for the seasonal virus, only pandemic virus genotypes were detected. These adapted pandemic strains did, however, contain two nonsynonymous mutations (hemagglutinin K154Q and polymerase acidic protein L295P) that conferred a more virulent phenotype, both in cell cultures and in ferrets, than their parental strains.

 

The polymerase acidic protein mutation increased polymerase activity at 37°C, and the hemagglutinin change affected binding of the virus to α2,6-sialyl receptors. When the seasonal A/H1N1 virus was initially present in excess, the dominant progeny virus was a reassortant containing the hemagglutinin gene from the seasonal strain and the remaining genes from the pandemic virus.

 

Our study demonstrates that the emergence of an A/H1N1 pandemic strain of higher virulence is possible and that, despite their lack of detection thus far in humans, viable seasonal/pandemic virus reassortants can be generated.

 

IMPORTANCE This report supplies a key piece of information for investigating future evolution scenarios of pandemic A/H1N1 influenza in the human population.

 

We report that the emergence of an A/H1N1 pandemic strain of higher virulence is possible and that, despite their lack of detection thus far in humans, viable seasonal/pandemic virus reassortants can be generated.

 

 

Influenza viruses change, evolve, or mutate over time via two well established routes; Antigenic drift and Antigenic Shift.

 

Antigenic drift causes small, incremental changes in the virus over time.   Drift is the standard evolutionary process of influenza viruses, and often come about due to replication errors that are common with single-strand RNA viruses.

 

Shift occurs when one virus swap out chunks of their genetic code with gene segments from another virus.  This is known as reassortment. While far less common than drift, shift can produce abrupt, dramatic, and sometimes pandemic inducing changes to the virus.

 

For shift to happen, a host (human, swine, bird) must be infected by two influenza viruses at the same time.  While that is relatively rare, it does happen.

 

 

 

Without getting too detailed (you can read the report for yourself), what the researchers here have done is to co-infect normal human bronchial epithelial (NHBE) cells in vitro with varying ratios of two influenza viruses; the 2009 H1N1 strain and an older (Tamiflu resistant) seasonal H1N1.

 

Although not a perfect model for the human model (NHBE lack the immune response that humans would mount), this is believed to be a reasonable test platform for viral reassortment and/or mutation.

 

In the end, while in most cases the novel H1N1 strain predominated, two nonsynonymous mutations (labeled G1 and G2) were identified and analyzed. 

 

Ferret testing showed that both mutated strains produced higher viral titers, and longer virus shedding, than their parental counterparts.

Ferrets infected with the G1 strain demonstrated substantially more necrotizing bronchiolitis and alveolitis than test animals infected with G2, or either of the parental strains.

 

Leading the authors to state:

 

Taken together, our findings showed that two variants selected by coinfection of human cells acquired increased replicative fitness and virulence both in vitro and in vivo

 

From the discussion portion of the study, they authors write:

 

Our findings suggest that generation of viable intrasubtype reassortment between currently circulating oseltamivir-resistant seasonal and pandemic viruses is possible but requires initial dominance of the seasonal A/H1N1 strain.

 

Although we did not observe the emergence of a drug-resistant reassortant, the G2 variant was more fit than its parental strains for replication in ferrets. The lack of detection of such reassortants before now may be explained by a too-low ratio of seasonal to pandemic A/H1N1 strains.

 

 

With very little known co-circulating seasonal H1N1 at this time, opportunities for a reassortment of the novel H1N1 virus are admittedly slim. The authors state that the odds currently favor evolution via a less radical antigenic drift rather than an abrupt shift.

 

But that could change over time. There are other potential contributor viruses beyond seasonal H1N1, such as H5N1.

 

And changes via antigenic drift could enhance virulence as well.

 

So the authors suggest that future surveillance of the novel H1N1 virus watch for the adaptive changes identified in this study, as they may serve as a possible early warning sign of increased virulence in the virus.

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