TSRI: H7N9 Virus Still Binds Preferentially to Avian Receptors

Binding of H7N9 to Avian Receptors

Credit: Rui Xu, The Scripps Research Institute

 

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Research over the summer has repeatedly suggested that the newly emerging H7N9 virus in China is better adapted to mammalian hosts than many other avian influenza viruses we’ve previously seen (see Science: H7N9 Transmissibility Study In Ferrets & Nature: Limited Airborne Transmission Of H7N9 Between Ferrets), giving rise to the concern that this virus might be close to sparking a pandemic.

 

Yet, despite these findings, only a handful of small clusters of human infection have been documented, and the vast majority of contacts of known cases never become infected.

 

While the virus appears more readily transmitted from birds to humans than say, the H5N1 virus . . .  it has not yet shown the crucial ability to transmit efficiently from one human to another.   

 

Viruses constantly change, of course, and no one is entirely sure what change (or more likely, what combination of changes) are needed to fully `humanize’ this virus.

 

Influenza viruses have an RBD - Receptor Binding Domain (the area of its genetic sequence that allows it to attach to, and infect, host cells) that – like a key slipping into a padlock -`fit’ the receptor cells commonly found in their preferential host.

 

Avian adapted flu viruses, like the H5N1 virus, bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds, while `humanized’ flu viruses have an affinity for the alpha 2,6 receptor cells most commonly found in the human respiratory system. .

 

While there are some α2-3 cells deep in the lungs of humans – which may explain the high rate of pneumonia in the unlucky few who do contract avian flu -  for an influenza to be truly successful in a human host, it needs to a able to bind to the α2-6  receptor cells in the upper airway.

 

Today, The Scripps Research Institute (TSRI) has published their analysis of the receptor binding of the H7N9 virus to both human, and avian, receptor cells.  And while this virus does, indeed bind weakly to human α2-6 receptor cells, it still shows a strong preference to bind to avian α2-3 cells.

 

First a link to the study, then some excerpts from the press release.

Preferential Recognition of Avian-Like Receptors in Human Influenza A H7N9 Viruses

Rui Xu, Robert P. de Vries, Xueyong Zhu, Corwin M. Nycholat, Ryan McBride, Wenli Yu, James C. Paulson,Ian A. Wilson

Editor's Summary

The 2013 outbreak of avian-origin H7N9 influenza in eastern China has raised concerns about its ability to transmit in the human population. The hemagglutinin glycoprotein of most human H7N9 viruses carries Leu²²⁶, a residue linked to adaptation of H2N2 and H3N2 pandemic viruses to human receptors. However, glycan array analysis of the H7 hemagglutinin reveals negligible binding to humanlike α2-6–linked receptors and strong preference for a subset of avian-like α2-3–linked glycans recognized by all avian H7 viruses. Crystal structures of H7N9 hemagglutinin and six hemagglutinin-glycan complexes have elucidated the structural basis for preferential recognition of avian-like receptors. These findings suggest that the current human H7N9 viruses are poorly adapted for efficient human-to-human transmission.

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Scripps Research Institute

TSRI scientists: Emerging bird flu strain is still poorly adapted for infecting humans

LA JOLLA, CA—December 5, 2013—Avian influenza virus H7N9, which killed several dozen people in China earlier this year, has not yet acquired the changes needed to infect humans easily, according to a new study by scientists at The Scripps Research Institute (TSRI). In contrast to some initial studies that had suggested that H7N9 poses an imminent risk of a global pandemic, the new research found, based on analyses of virus samples from the Chinese outbreak, that H7N9 is still mainly adapted for infecting birds, not humans.

"Luckily, H7N9 viruses just don't yet seem well adapted for binding to human receptors," said Ian A. Wilson, the Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI.

"Because publications to date have implied that H7N9 has adapted to human receptors, we felt we should make a clear statement about this," said James C. Paulson, chair of TSRI's Department of Cell and Molecular Biology.

The Wilson and Paulson laboratories collaborated on the study, which is reported in the December 6, 2013 issue of the journal Science.

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Study: Calming The Cytokine Storm

 

 

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Some fascinating research coming out of The Scripps Research Institute today that looks at what may turn out to be a new way of treating serious illness due to influenza.  

 

Rather than trying to combat the virus – which has a nasty habit of evolving resistance to antivirals - they are looking at ways of reducing the body’s sometimes excessive immune response known as a Cytokine Storm.

 

Right now their research has been conducted on mice, and it is helping to unlock the long standing mystery of how and where cytokines are produced. 

 

Cytokines are a category of signaling molecules that are used extensively in cellular communication. They are often released by immune cells that have encountered a pathogen, and are designed to alert and activate other immune cells to join in the fight against the invading pathogen.

 

This cascade of immune cells rushing to the infection, if it races out of control, can literally kill the patient. Their lungs can fill with fluid (which makes a terrific medium for a bacterial co-infection), and cells in the lungs (Type 1 & Type II Pneumocytes) can sustain severe damage.

 

Previously, in Swine Flu Sequelae and Cytokine Storm Warnings, we looked at some of the severe lung damage during the 2009 pandemic that was thought to be due to this overreaction of the immune system.

 

All of which serves as prelude to a study published today in the Journal Cell with the somewhat daunting title of:

 

Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus Infection

 

Cell, Volume 146, Issue 6, 980-991, 16 September 2011  10.1016/j.cell.2011.08.015

Authors

John R. Teijaro, Kevin B. Walsh, Stuart Cahalan, Daniel M. Fremgen, Edward Roberts, Fiona Scott, Esther Martinborough, Robert Peach, Michael B.A. Oldstone, Hugh Rosen

 

No worries. 

 

We have two explanations available to us, one pretty basic, and a second with more meat to it.

First, the basics from a Cell Press Release.

 

Avoiding fatal responses to flu infection

Most of the time, being ill with the flu is little more than a nuisance. Other times, it can spark an exaggerated immune response and turn deadly. Researchers reporting in the September 16th issue of the journal Cell, a Cell Press publication, have now traced the origins of this severe immune response -- called a cytokine storm -- to its source.

 

Cytokines are the chemical signals that drive inflammation, and cytokine storms are thought to be the cause of many of the deaths attributed to the 1918 worldwide influenza pandemic and to the more recent outbreaks of swine and bird flu infection. The new study provides encouraging news by offering the foundations for a completely new kind of flu therapy.

 

"We are showing for the first time that you can actually separate the deleterious events from those needed to control the virus," said Hugh Rosen, senior author of this study, from The Scripps Research Institute.

 

"It had been thought for a long time that all injury from influenza was due to the virus itself, consequently, and rationally, the focus was on developing antiviral drugs," said study co-author Michael Oldstone, also of Scripps.

 

The new results suggest that drugs aimed at the dangerous immune response may offer a life-saving new line of defense, by protecting infected hosts from themselves. Another bonus is that such an approach doesn't put the same pressure on viruses to adapt and develop drug resistance.

 

The cytokines associated with flu infection were thought to come from virus-infected cells found primarily in the lungs and nasal passages. The authors find that the cytokines are instead released from the endothelial cells that line blood vessels. A protein found on the surface of endothelial cells, called Sphingosine-1-phosphate receptor (S1P1), is essential for flu-associated cytokine storms.

 

In mice treated with a molecule that targets S1P1, cytokine production and the early signs of inflammation are suppressed. As a result, the animals are much more likely to survive infection with H1N1 swine flu virus. Notably, several companies are already testing S1P1-targeted drugs in clinical trials, the researchers say.

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A more in-depth explanation can be found in The Scripps Research Institute’s press room.

 

 

Scripps Research Team Discovers Treatable Mechanism Responsible for Often Deadly Response to Flu

LA JOLLA, CA – September 15, 2011 – Researchers at The Scripps Research Institute have found a novel mechanism by which certain viruses such as influenza trigger a type of immune reaction that can severely sicken or kill those infected.

 

This severe immune reaction—called a “cytokine storm”—floods the tiny air sacs of the lungs with fluid and infection-fighting cells, blocking off airways and damaging body tissues and organs. Cytokine storms are believed to have played a major role in the staggering mortality of the 1918-1919 worldwide influenza pandemic, as well as in the more recent swine flu and bird flu outbreaks.

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And lastly, in concert with the publication of this study, two of the primary researchers - Professors Michael BA Oldstone and Hugh Rosen – discuss their findings in the following video.

 

 

 

Like I say, it’s fascinating stuff. 

 

And while it won’t produce an FDA approved flu drug anytime in the near future, research like this helps show us how the immune system works, and that in turn opens up new avenues of exploration for tomorrow's drugs.