Renewed Respect For Wild H5N1

 

# 6315

 

 

Part of the fallout from the publication of Yoshiro Kawaoka’s research paper (see Nature Publishes The Kawaoka H5N1 Study) has been renewed concerns over the progress the avian flu virus is making in the wild and its potential for sparking a pandemic.

 

A few headlines from the past 24 hours include:

 

Once-Banned Bird Flu Study Suggests Pandemic Threat Is Real Newsday.com

 

Bird flu viruses have potential to cause a ‘human pandemic' The Hindu

 

Study Shows How Bird Flu Could Jump to Humans - MedPage Today

 

Pandemic Potential? Bird Flu Becomes Airborne With Just 4 Mutations LiveScience.com

 

 

Kawaoka showed that it would take perhaps only 3 or 4 mutations to turn the H5N1 virus into a mammalian transmissible influenza, and noted that similar genetic changes have already been observed in virus samples collected from the middle east.

 

The `money quote’ from his paper was:

 

Therefore, these viruses may be several steps closer to those capable of efficient transmission in humans and are of concern.

 

 

Kawaoka references a 2011 study that found that several new H5 sublineages have emerged in Egypt with an increased affinity for (human) α2,6 SA receptor cells while still retaining their binding ability to (avian) α2,3 SA receptor cells.

 

We looked at this paper roughly a year ago in PLoS: Human-Type H5N1 Receptor Binding In Egypt.

 

Of note, in 2011 the authors found `increased attachment and infectivity in the human lower respiratory tract, but not in the larynx.’

 

Many scientists believe the virus must learn to bind to, and replicate in, the upper airway (nose, larynx, pharynx, trachea)  of humans in order to transmit efficiently from human to human. 

 

And that hasn’t happened in the wild yet.

 

Of concern, one of Kawaoka’s discoveries is a single mutation that `stabilizes’ the virus so that it can replicate within the pH range normally found in the trachea.

 

Some scientists worry that this pH stabilization might be one of the last big hurdles the virus must clear before becoming more of a human threat.

 

Whether the `right’ mutations will occur in nature, and at a time and place conducive for sparking a pandemic, is subject to debate. 

 

Some scientists argue that if it hasn’t happened by now, it isn’t likely to.

 

But it now appears that the number changes needed for the H5N1 virus to make a leap from being an avian-specific virus to a human-adapted one may be fewer than previously suspected.

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Study: Dual Receptor Binding H5N1 Viruses In China

 

(Very Simplified Illustration of RBDs)

# 6238

 

 

Human adapted 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 the human upper respiratory tract; the alpha 2,6 receptor cell.  

 

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 there are some alpha 2,3 cells deep in the lungs of humans, for an influenza to be successful in a human host, it needs to a able to bind to the a 2,6 receptor cell.

 

A design flaw that - at least for the time being – is believed to have kept the H5N1 virus from taking off in the human population (note: there are likely other genetic barriers as well).

 

All of which serves as prelude to a study out of China where researchers have found at least two strains of the H5N1 virus that demonstrated the ability to bind to both a2,3 and a2,6 receptor cells.

Before anyone starts to head down to the bunker, these viruses were collected between 2003 and 2009, and despite their ability to bind to human-type receptors (at least at high viral loads), they have not managed to spark a pandemic.

The following excerpts come the abstract that appears in Biomedical and Environmental Sciences, Volume 25, Issue 1(h/t Tetano on FluTrackers for this link). 

Follow the link to read it in its entirety.

 

Identification of Dual Receptor-binding Specific Strains of Human H5N1 Viruses in China

Jian Fang ZHOU, Shu Mei ZOU, Zi LI, Min WANG, Jie DONG, Jun Feng GUO, He Jiang WEI, Le Ying WEN, Hong XU, Yue Long SHU

Abstract (excerpts):

 

 

<SNIP>

Results Dual binding preference to 2, 3 and 2, 6-glycans were found in two strains: A/Guangdong/1/06 (A/GD/1/06) and A/Guangxi/1/08 (A/GX/1/08). Though minor effect of short-2, 6-binding was detected in A/GX/1/08 at a low virus titer, both showed high affinity to the oligosaccharide at a high load. Notably both are of the long-2, 6-recognition, with the same topology as that of human H1N1 and H3N2 viruses.

Conclusion The findings suggest that human H5N1 virus in China likely acquired the potential human-adaptation ability. Further research and surveillance on receptor-binding specificity of H5N1 viruses are required.

 

 

 

While a significant step towards adaptation to human hosts, obviously something more is needed to make the H5N1 virus a pandemic threat.

 

Lest anyone be too comforted, this study does show that the H5N1 virus is capable of evolving towards a more `humanized’ pathogen.

 

Which is why the world remains at pre-pandemic Phase III on the H5N1 virus, and we continue to watch for signs of better adaptation to humans.

 

 

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Virology Journal: Receptor Cells In Minor Poultry Species

 

 

 

# 5136

 

 

Constant 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 influenzas – on the other hand - are adapted to bind to the kind of receptor cells that line the surfaces of the human respiratory system; alpha 2,6 receptor cells.

 

While not an absolute, flu viruses that bind to one type of receptor cell, tend not to bind to the other.

 

This ability to bind to a specific type of cell has often been described as the host cell being a padlock, and the virus needing a specific key (determined by the genetics of the virus’s Receptor Binding Domain: RBD) to unlock it.

 

 

(A Very Simplified Illustration of RBDs)

 

Now humans do have some avian-like alpha 2,3 receptor cells, particularly deep in the lungs.

 

This has been suggested as the reason that - when on rare occasions humans contract H5N1 - it is usually a deep lung infection.

 

It has also been postulated that H5N1’s deeper lung infections may reduce human-to-human transmission, as sneezing is a less common symptom.   

 

The concern is that over time, the H5N1 (or some other avian flu) virus might mutate in such a way as to be able to bind to human α2,6 receptor cells.

 

And while that may not be the only obstacle keeping the virus from becoming a pandemic strain, it does appear to be a major one.

 

The two main ways the virus could `learn’ to adapt to humans are through a mutation, or through a reassortment (a sharing of genetic material) with another flu virus.

 

It is possible for a simple mutation to change the binding preference of an influenza strain, to allow it to bind to a different type of receptor cell (or, to more than one type).

 

This is actually something we’ve observed with the novel H1N1 virus.  The D222G  or ``Norway’ mutation has been shown to convey dual receptor specificity for complex α2,3 and α2,6-linked sialic acids (see  Study: Receptor Binding Changes With H1N1 D222G Mutation).

 

 

Since pigs are known to have both types of receptor cells, they have often been cited as a potential `mixing vessel’ for influenza strains.  

 

 

 

 

Last January I wrote a blog titled Mixing Vessels For Influenza  which mentioned research done by two wildlife disease experts from the San Diego Zoo - Mark Schrenzel and Bruce Rideout – that identified the North American Striped Skunk and the Persian leopard - along with a handful of other small carnivores - as a potential host for influenza reassortment.

 

Additionally, we’ve seen H5N1 infections among dogs, cats, civets, raccoons, martens, and – of course – humans.   And researchers have successfully infected cattle with the H5N1 virus, along with ferrets and mice for testing.

 

But since avian strains mostly infect birds, the opportunities for avian viruses to encounter human adapted viruses, or to learn to unlock alpha 2,6 receptor cells, are limited. 

 

But perhaps, not quite as limited as we have previously believed.

 

Which brings us to today’s study, from the Virology Journal, that looks at types of receptor cells detected in a half dozen minor species of poultry.

 

The condensed version is, some types of poultry have both types of receptor cells . . . but read the entire abstract, or better yet, the entire article.

 

 

Characterization of influenza virus sialic acid receptors in minor poultry species

Brian Kimble, Gloria Ramirez Nieto and Daniel R Perez

It is commonly accepted that avian influenza viruses (AIVs) bind to terminal alpha2,3 sialic acid (SA) residues whereas human influenza viruses bind to alpha2,6 SA residues.

 

By a series of amino acid changes on the HA surface protein, AIVs can switch receptor specificity and recognize alpha2,6 SA positive cells, including human respiratory epithelial cells.

 

Animal species, like pigs and Japanese quail, that contain both alpha2,3 and alpha2,6 SA become ideal environments for receptor switching. Here, we describe the SA patterns and distributions in 6 common minor domestic poultry species: Peking duck, Toulouse geese, Chinese ring-neck pheasant, white midget turkey, bobwhite quail, and pearl guinea fowl.

 

Lectins specific to alpha2,3 and alpha2,6 SA (Maakia amurensis agglutinin and Sambuca nigra agglutinin, respectively) were used to detect SA by an alkaline phosphotase-based method and a fluorescent-based method.

 

Differences in SA moieties and their ability to bind influenza viruses were visualized by fluorescent labeling of 4 different H3N2 influenza viruses known to be specific for one receptor or the other.

 

The geese and ducks showed alpha2,3 SA throughout the respiratory tract and marginal alpha2,6 SA only in the colon.

 

The four other avian species showed both alpha2,3 and alpha2,6 SA in the respiratory tract and the intestines. Furthermore, the turkey respiratory tract showed a positive correlation between age and alpha2,6 SA levels.

 

The fact that these birds have both avian and human flu receptors, combined with their common presence in backyard farms and live bird markets worldwide, mark them as potential mixing bowl species and necessitates improved surveillance and additional research about the role of these birds in influenza host switching.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

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ICEID: Nasal Polyps And Bird Flu

 

 

# 4719

 

 

 

Earlier today I wrote about the ICEID 2010 conference underway in Atlanta, and gave the link to the slide presentation abstracts.

 

While there are a great many presentations of note, one explores a theory I confess, I’d not heard before;

That nasal polyps and/or allergic rhinitis might make one more susceptible to contracting H5N1.

 

First the abstract, then a little discussion.

 

 

Enhanced Susceptibility of Nasal Polyp Tissues to Avian and Human Influenza Viruses

P. Auewarakul, O. Suptawiwat, P. Tantilipikorn, C. Boonarkart, P. Puthavathana; Mahidol
University, Bangkok, THAILAND

 
Background: Influenza viruses bind and infect respiratory epithelial cells through sialic acid on cell
surface. Differential preference to sialic acid types contributes to host- and tissue-tropism of avian and
seasonal influenza viruses.

 

Although the highly pathogenic avian influenza virus H5N1 can infect and cause severe diseases in humans, it is not efficient in infecting human upper respiratory tract. This is because of the scarcity of its receptor, 2,3-linked sialic acid, in human upper airway. Expression of sialic acid can be influenced by various factors including inflammatory process.

 

Allergic rhinitis and nasal polyp are common inflammatory conditions of nasal mucosa and may affect expression of the sialic acid and susceptibility to influenza infection.

 

Methods: To test this hypothesis, we detected 2,3- and 2,6-linked sialic acid in human nasal polyp and normal nasal mucosal tissues by lectin staining and infected explants of those tissues with avian influenza viruses H5N1 and seasonal influenza viruses.

Results: We show here that mucosal surface of nasal polyp expressed higher level of 2,3- and 2,6-linked sialic acid than normal nasal mucosa. Accordingly, nasal polyp tissues explants were more susceptible to both H5N1 avian influenza viruses and seasonal influenza viruses.

 

Our data suggest a role of nasal allergic conditions in susceptibility to influenza infection, especially by avian influenza viruses, which is generally
inefficient in infecting human upper airway.

 

Conclusions: The increased receptor expression may contribute to increased susceptibility in some individuals.

 

This may contribute to the gradual adaptation of the virus to human population.

 

 

Nasal polyps are small edematous grape-like sacs, filled with inflammatory cells and fluid, than can sometimes develop deep inside the nasal cavity.

 

They can appear singly or in clusters, and may come about as a result of long-standing inflammation, although often the cause is never known.

 

 

I’ll wait while everyone goes `eeewww’.

 

Ok, to continue.

 

In order to infect a host, a virus must attach itself to cells in the host’s body.  Influenza viruses have an affinity for either the alpha 2,3 receptor cell or the alpha 2,6 receptor cell.

 

Avian adapted influenza viruses bind preferentially to Alpha 2,3 receptor cells, which are commonly found in the digestive tract of birds.  This explains why most avian flu viruses are gastrointestinal infections in birds.

 

Human adapted viruses have an affinity for the alpha 2,6 receptor cell, which populate the upper airway and lungs.  This is why influenza is a respiratory virus in humans.

 

There are some crossovers in receptor cells, and humans have some avian-like alpha 2,3 receptor cells, but most are deep in the lungs.  It is harder for avian influenzas to reach those cells, but not impossible.

 

According to this research, however, inflammation processes – such as allergic rhinitis and nasal polyps – generate increased alpha 2,3 and alpha 2,6 receptor cells in the upper airway.

 

Which, theoretically anyway, could increase the odds of human acquisition of the H5N1 virus.

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