Study: Adaptation Of H6N1 From Avian To Human Receptor-Binding

Flu Virus binding to Receptor Cells – Credit CDC

 

# 10,019

 

A couple of days ago in EID Journal: Seropositivity For H6 Influenza Viruses In China, we looked at a study that found a low, but significant level of antibodies – particularly among live bird handlers – to the avian H6 virus in China.  This study was published not quite two years after the Taiwan CDC Reported the Human Infection With Avian H6N1.

 

The H6N1 virus has been around for decades in Chinese poultry - it possesses similar internal genes to H5N1 and H9N2 (cite 2002 J Virol  Molecular evolution of H6 influenza viruses from poultry in Southeastern China by Webster, Webby, Shortridge  et al.) - and it has been speculated that it may have been involved in the genesis of H5N1 in Hong Kong in 1997.

 

While viewed with some suspicion by virologists 15 years ago, once H5N1 emerged into the limelight again in 2003, H6N1 as a possible human threat receded back into the shadows.  It was still studied as an avian threat, of course (see 2007’s Establishment of influenza A virus (H6N1) in minor poultry species in southern China), as it continued to spread (and reassort) across Southeast Asia.

 

The discovery of the virus in a 20 year-old woman with pneumonia in Taiwan two years ago has, understandably, renewed interest in this viral contender, and we’ve seen a flurry of new studies as a result.

 

• Last March, in Avian Flu Antibody Survey In Poultry Workers – Taiwan 2012, we looked at a study that looked for antibodies to H5N2, H6N1, H7N3 and H7N9 among hundreds of subjects, and while they found a fairly low incidence of antibodies overall (max 2.99% for H5N2 in poultry vendors), only found one positive for H6N1.
• Also last March, in TSRI: H10N8 and H6N1 Bind Poorly To Human Receptor Cells - while ostensibly good news – researchers warned that both of these viruses bind differently than other avian viruses we’ve seen, and that our understanding of how these viruses mutate isn’t complete enough to warrant complacency.
• And in late 2013, the Taiwan CDC: Epidemiological Analysis Of Human H6N1 Infection, warned that a (emphasis mine)  “unique clade of H6N1 viruses with a G228S substitution of haemagglutinin have circulated persistently in poultry in Taiwan. These viruses continue to evolve and accumulate changes, increasing the potential risk of human-to-human transmission.”

 

While one (known) human infection pales against the hundreds of H5N1 and H7N9 infections we’ve see over the past decade – it is one more than we’ve seen from H5N8, H5N2, and H5N3 - and it hints as to what is possible down the road.  

 

To this mix we add a new study, published in the EMBO Journal, that finds recent and worrisome changes in the receptor binding characteristics of the H6N1 virus.  Changes they maintain have steadily moved the virus towards an affinity towards human receptor cells instead of avian receptor cells.

 

Note: The G228S substitution mentioned in the Taiwan CDC report above plays heavily in this study.

 

First the abstract, then I’ll return with a bit more:

 

Adaptation of avian influenza A (H6N1) virus from avian to human receptor-binding preference

Fei Wang^1,2,†, Jianxun Qi^2,3,†, Yuhai Bi^2,3, Wei Zhang^2,3, Min Wang^1,2, Baorong Zhang^4,5, Ming Wang¹, Jinhua Liu¹, Jinghua Yan^2,3, Yi Shi^2,3,4 and George F Gao^{1,2,3,4,6,7,*}

Article first published online: 4 MAY 2015

Abstract

The receptor-binding specificity of influenza A viruses is a major determinant for the host tropism of the virus, which enables interspecies transmission. In 2013, the first human case of infection with avian influenza A (H6N1) virus was reported in Taiwan. To gather evidence concerning the epidemic potential of H6 subtype viruses, we performed comprehensive analysis of receptor-binding properties of Taiwan-isolated H6 HAs from 1972 to 2013. We propose that the receptor-binding properties of Taiwan-isolated H6 HAs have undergone three major stages: initially avian receptor-binding preference, secondarily obtaining human receptor-binding capacity, and recently human receptor-binding preference, which has been confirmed by receptor-binding assessment of three representative virus isolates. Mutagenesis work revealed that E190V and G228S substitutions are important to acquire the human receptor-binding capacity, and the P186L substitution could reduce the binding to avian receptor. Further structural analysis revealed how the P186L substitution in the receptor-binding site of HA determines the receptor-binding preference change. We conclude that the human-infecting H6N1 evolved into a human receptor preference.

Synopsis

Historical analysis of influenza H6N1 isolates from 1972 until 2013, when the first human infection occurred, reveals amino acid changes that change receptor binding preference from birds to humans and therefore virus ability to cross the species barrier.

• Human-infecting avian influenza H6N1 has gained human receptor binding preference.
• H6N1 HA has changed binding preference in at least two steps.
• First, E190V and G228S substitutions provide human receptor binding ability.
• Subsequently, P186L substitution reduces avian receptor binding, and provides human receptor binding preference.

 

For an influenza virus to infect a host, the virus must bind (attach) itself to the surface of a cell.  To do that influenza viruses have an RBS - Receptor Binding Site (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 host’s receptor cells.

 

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, most researchers believe it needs to a able to bind to the α2-6 receptor cell found in the upper airway (trachea).

 

Although a preferential binding to human receptor cells is considered perhaps the biggest obstacle for an avian virus to successfully jump species – it isn’t the only one.

 

Another major requirement is the ability to replicate efficiently at the lower temperatures found in the upper respiratory system of humans, as opposed to the hotter gastrointestinal system of birds.  There are other factors – some we know about, others we don’t – that must come together properly to allow an avian virus to jump species successfully.

 

All of which means that even with an improved receptor binding ability, the H6N1 virus may be far from being ready for prime time.

 

But it does mean that H6N1 is legitimately a virus worth watching, both for further evolutionary changes, and for how it behaves in poultry and in humans.

J. Virology: Genetics, Receptor Binding & Virulence (in Mice) Of Avian H10N8

Flu Virus binding to Receptor Cells – Credit CDC

 

# 9924

 

With all of the attention being given to the H7 and H5 avian flu strains this winter (see The Transmission Potential Of A(H7N9) In China & WHO: H5 Currently The Most Obvious Avian Flu Threat) it is easy to forget there are other avian subtypes on our radar as well. 

 

We’ve seen a handful of scattered H9N2 infections over the years, and even a one-off H6N1 in Taiwan in 2013. There’s a reservoir of mixed-host (avian, swine, equine, canine, etc.) H1, H2 & H3 viruses worthy of our attentions, as well.

 

But bringing up the rear are the H10 avian viruses, which have made a splash in the past few years.

 

Last fall, in Avian H10N7 Linked To Dead European Seals, we looked at the die off of thousands of harbor seals due to a combination of avian H10N7 influenza, pneumonia, and bacterial infection.  While known human infections with avian H10 viruses are limited, we’ve discussed them previously on several occasions. 

 

• In 2004, the first known human infections were reported among two Egyptian toddlers, as described in the  WHO/CDS/CSR/RMD report Avian Influenza Virus A (H10N7) Circulating among Humans in Egypt.
• And again, in 2012, in EID Journal: Human Infection With H10N7 Avian Influenza, we looked at a limited outbreak among workers with only mild symptoms at a chicken farm in Australia. 
• And perhaps most concerning, we saw three severe infections with an H10N8 virus in China last winter.

 

A little over a month ago, in TSRI: H10N8 and H6N1 Bind Poorly To Human Receptor Cells, we saw an encouraging report suggesting that neither subtype was poised to pose a serious pandemic threat, although they warned that these viruses bind differently than other avian viruses we’ve seen, and that our understanding of how these viruses mutate isn’t complete enough to warrant complacency.

 

All of which serves a prelude to a new study, published on April 8th in the Journal of Virology, that examines the genetic diversity, and behavior, of eight H10N8 viruses collected between 2009 and 2013. 

 

Worth noting:

• The genetic diversity (5 genotypes) detected among ducks and chickens
• Seven of the eight viruses replicated well in the lungs of mice
• Differences in virulence (in mice) between duck and chicken genotypes
• Dual binding to both Human (a2,6) and avian (a2,3) receptor cells, albeit with marked preference for avian receptors.
• The role that H9N2 has played in its evolution

 

The entire study, including an array of graphs and charts, is available at:

 

Genetics, receptor binding, and virulence in mice of H10N8 influenza viruses isolated from ducks and chickens in live poultry markets in China

Guohua Denga, Jianzhong Shia,  Jing Wanga, Huihui Konga,  Pengfei Cuia, Fang Zhanga,  Dan Tana, Yasuo Suzukib, Liling Liua, Yongping Jianga, Yuntao Guana and Hualan Chena⇑

ABSTRACT

We analyzed eight H10N8 viruses isolated from ducks and chickens in live poultry markets from 2009 to 2013 in China. These viruses showed distinct genetic diversity and formed five genotypes: the four duck isolates formed four different genotypes, whereas the four chicken viruses belong to a single genotype. The viruses bound to both human- and avian-type receptors, and four of the viruses caused 12.7% – 22.5% body weight loss in mice.

SUMMARY

In summary, our genetic studies indicate that the four duck viruses belong to four different genotypes, suggesting that they were introduced into ducks independently; the four chicken viruses belong to one genotype and appear to be hybrids of a duck virus and the local H9N2 viruses (Table 1).

The ability of H10N8 viruses to bind to human-type receptors facilitates their infection of humans, as occurred with the H7N9 viruses (28).

The more efficient replication in mice of the viruses isolated in Jiangxi province than the three duck viruses isolated in Hunan province suggests that the internal genes of the H9N2 viruses may have further increased the replicative ability and virulence of H10N8 viruses in mammals; of cause, the surface proteins may have also contributed to the difference of the virulence.

Although the viruses in our studies were all isolated from healthy birds, two H10 influenza viruses, A/turkey/England/384/79 and A/mandarin duck/Singapore/805/F-72/7/93, were reported to be highly pathogenic in chickens (3, 30). Therefore, it is important to continue monitoring the evolution of H10N8 influenza viruses and to evaluate their potential to cause disease in poultry and pandemics in humans.

 

As we’ve seen with the H5N1 and H7N9 viruses, H10N8 continues to evolve and the ubiquitous H9N2 virus appears to play a substantial role in its evolution.  An LPAI virus in chickens, H10N8 (like H7N9) can spread stealthily between flocks without the typical warning signs that HPAI viruses provide, making it more difficult to detect and eradicate.

 

While the general consensus is that the H10 family of avian viruses aren’t `ready for primetime’, H10N8 has already shown the ability to produce serious (even fatal) illness in humans, which elevates its profile when compared to many other less virulence avian strains.

 

Add in its growing genetic diversity, and its ability to reassort with other avian flu viruses, and H10N8 deservedly holds a second tier position on our list of avian flu viruses to watch.

TSRI: H10N8 and H6N1 Bind Poorly To Human Receptor Cells

Flu Virus binding to Receptor Cells – Credit CDC

 

# 9818

 

Considering the recent spate of worrisome H5 and H7N9 bird flu news, I’m happy to report that at least two recently emerged avian viruses haven’t yet acquired one of the main traits that would allow them to become serious pandemic threats; the ability to bind preferentially to human receptor cells.

While our gaze has been focused primarily on H5N1 and H7N9, in the summer of 2013 Taiwan reported the first known human infection with an avian H6N1 virus, and a few months later mainland China reported the first three cases of H10N8 (two fatal). 

 

While only four cases were recorded, they – along with H5N6, and the globe-trotting H5N8 avian virus and its descendents – have shown just how quickly new subtypes can emerge.

 

Luckily, turning up in a small handful of cases is a far cry from being ready for prime time.

Human adapted influenza viruses have an RBS - Receptor Binding Site (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.

 

While avian adapted flu viruses, like the H5N1 virus, bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds.

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

 

There are other requirements – some we know about, others we don’t – that determine how well a virus can infect, replicate, and transmit in humans.  The ability to replicate at the lower temperatures found in the upper respiratory system is one of them. 

 

But first, and foremost, the virus must be able to bind to human receptor cells.

 

And here, the news on these two viruses remains encouraging.  

 

The journal Cell, Host & Microbe carries a pair of studies this week that look at the binding properties of these viruses, and both find they fall short.  While behind a pay wall,  we do have a press release from the The Scripps Research Institute (TSRI)  which provides some welcome details.

Links to the studies, and excerpts from the press release, follow:

 

Structure and Receptor Binding of the Hemagglutinin from a Human H6N1 Influenza Virus

Netanel Tzarum, Robert P. de Vries, Xueyong Zhu, Wenli Yu, Ryan McBride, James C. Paulson, Ian A. Wilson

Highlights

• The human H6N1 HA receptor binding site is distinct from other avian and human HAs
• The HA of a human H6N1 influenza virus retains avian receptor specificity
• The interactions of H6 HA with avian receptor analogs differ from other HAs
• Additional mutations are required to switch H6 HA to human receptor specificity

(Continue . . .)

 

A Human-Infecting H10N8 Influenza Virus Retains a Strong Preference for Avian-type Receptors

Heng Zhang, Robert P. de Vries, Netanel Tzarum, Xueyong Zhu, Wenli Yu, Ryan McBride, James C. Paulson, Ian A. Wilson

Highlights

• Human influenza H10N8 HA has negligible binding to human-like receptors
• Human influenza H10N8 HA retains strong binding to avian-like receptors
• The human receptor orientation in H10 HA differs from most human HA complexes
• Mutations that switch specificity in pandemic viruses do not alter H10 specificity

          (Continue . . .)

 

While ostensibly good news, the press release from Scripps warns that both of these viruses bind differently than other avian viruses we’ve seen, and that our understanding of how these viruses mutate isn’t complete enough to warrant complacency.

 

Scripps Research Institute Study Shows Two New Flu Strains Do Not Yet Easily Infect Humans

But Great Versatility of Viruses Suggests Continued Caution

LA JOLLA, CA—March 11, 2015—Scientists at The Scripps Research Institute (TSRI) have analyzed a key protein from two influenza strains that recently began causing sporadic infections among people in China and Taiwan.

The analyses suggest that the flu viruses, variants of subtypes H10N8 and H6N1, have not acquired changes that would allow them to infect people easily and cause a much-feared pandemic.

Yet the studies also highlight the versatility that bird flu viruses apparently have in attaching to host cells.

“These bird flu viruses seem able to bind to receptors on host cells in different ways and thus can probably mutate in different ways to jump to humans—so we shouldn’t be complacent about our ability to predict the viral changes required to get a pandemic,” said Ian A. Wilson, Hansen Professor of Structural Biology and chair of TSRI’s Department of Integrative Structural and Computational Biology.

<SNIP>

Difficult to Predict

How did such bird viruses end up causing infections of people? “We suspect that sporadic cases of human infection by a bird flu virus can occur, even without a change in the receptor specificity, if the dose of the viral exposure is high enough and/or it gets deep into the lungs, where there are some flu-virus receptors like those found in birds,” said Tzarum, a research associate in the Wilson laboratory who was first author of the H6N1 paper.

Flu viruses with these HAs thus remain essentially bird viruses, with limited ability to infect humans. Yet further mutations that would enable a switch in preference to human receptors—and a potential global pandemic—are still possible.

The new TSRI analyses also show that, at the atomic scale, these new bird flu HAs bind to host-cell receptors in ways not observed in studies of other bird flu viruses—implying that the mutations required for the switch to human receptors may be different for different strains and inherently hard to know in advance.

“There appear to be no general rules for this switch among bird flu viruses,” said Tzarum.

Determining whether a bird flu strain has truly jumped the species barrier will therefore continue to require detailed receptor-binding and structural studies like these, Wilson said.

(Continue . . . )

Study: H5N5 Receptor Binding

Flu Virus binding to Receptor Cells – Credit CDC

 

# 9576

 

Lost in shadow of higher profile H5N1, H5N2, H5N8, and H5N6 viruses is the H5N5 avian virus, which first came to light in a 2011 report (see EID Journal: Novel H5N5 Avian Influenza Detected In China), which described the isolation of two novel reassortant HPAI H5N5 viruses from apparently healthy domestic ducks in Eastern China.

 

The author’s wrote:

In our study, the 2 reassortant influenza viruses (008 [H5N5] and 031 [H5N5]) and their 3 possible parent viruses (108 [H5N1], 909 [H5N1], and 013 [H6N5]) were all isolated from apparently healthy domestic ducks.

We speculate that domestic ducks may serve as reassortant vessels for creating new subtypes of influenza viruses. In view of the practice of raising ducks in a free-range system, these novel strains could be transmitted to other domestic poultry and even humans.

 

Several of the same authors wrote about additional isolates of the H5N5 virus in the journal Veterinary Microbiology  (see Characterization of three H5N5 and one H5N8 highly pathogenic avian influenza viruses in China), that were isolated in China in 2009-10, suggesting that the first detection wasn’t a fluke.   

 

Now the authors of both reports are back with additional information on the receptor binding traits of the H5N5 viruses they’ve isolated, which they published late last month in the journal Veterinary Microbiology.

 

Novel reassortant H5N5 viruses bind to a human-type receptor as a factor in pandemic risk

Qunhui Li^a, Xuan Wang^a, Zhao Gao^a, Zhongtao Sun^a, Zhu Cui^a, Zhiqiang Duan^a, Juan Li^a, Min Gu^a, Xiaoquan Wang^{a, b}, Jiao Hu^{a, b}, Xiaowen Liu^{a, b}, Xiufan Liu^{a, b,}

doi:10.1016/j.vetmic.2014.11.030

Highlights

• H5 viruses continue to spread geographically and evolve rapidly.

• Various NA subtypes of H5 HPAIVs have been detected in different domestic poultry.

• Some natural reassortant H5N5 HPAIVs were isolated from poultry in China.

• These H5N5 viruses bound to both α-2,3 and α-2,6 receptors.

• 031 virus replicated and transmitted efficiently in guinea pigs.

---

Abstract

Highly pathogenic avian influenza A(HPAI) H5N1 viruses pose a serious pandemic threat due to their virulence and high mortality in humans, and their increasingly expanding host range and significant ongoing evolution could enhance their human-to-human transmissibility. Recently, various reassortant viruses were detected in different domestic poultry, with the HA gene derived from the A/goose/Guangdong/1/96-like (Gs/GD-like) lineage and the NA gene from influenza viruses of other subtypes. It is reported that some natural reassortant H5N5 highly pathogenic avian influenza viruses were isolated from poultry in China. And their HA genes were belonged to a new clade 2.3.4.4. We evaluated the receptor binding property and transmissibility in guinea pigs of these reassortant H5N5 HPAIVs.

The results showed that these viruses bound to both avian-type (α-2,3) and human-type (α-2,6) receptors. In addition, we found that one of these viruses, 031, not only replicated but also transmitted efficiently in guinea pigs. Therefore, such reassortant influenza viruses may pose a pandemic threat.

In a bit of serendipitous timing, as I was pondering the unusual clade designation of 2.3.4.4 mentioned in the above study, ProMed Mail carried an announcement of a new WHO/OIE/FAO statement creating this new clade (see WHO/FAO/OIE Announce A New H5 Clade (2.3.4.4)), which I quickly posted.

 

While not `new’ in the sense of just recently appearing, this clade is now just formally being recognized as a separate branch off the H5 family tree.

 

Despite binding to both a2,3 and a2,6 receptor cells and (at least one strain) replicating well in guinea pigs, the fact that we aren’t already hip-deep in H5N5 infections tells us regardless of its potential, it isn’t yet ready for prime time. 

 

Influenza evolution may be inevitable, but random selection takes its own sweet time.

 

And going from an avian virus to a mammalian virus is a pretty good leap. There may even be an as yet unidentified `species barrier’ that would  effectively keep an H5 or H7 avian virus from fully adapting to mammal hosts (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?). 

 

Few influenza researchers, however, are willing to bet our collective futures on our being that lucky.

 

Avian adapted flu viruses bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds, while human-adapted influenza viruses bind to the alpha 2,6 receptor cells commonly found in the upper airway. 

 

Humans have some a2,3 cells deep in the lungs, which may help explain why avian influenza can sometimes jump to humans, and when it does, often causes severe pneumonia.

 

But birds run `hotter’ than mammals, and avian viruses replicate best in a bird’s gut, which is much warmer than the upper airway of humans.  Which means mammalian adapted viruses must also adapt to replicate at a lower temperature to be successful in humans.

 

These are just two examples of obstacles that must be overcome before an avian virus can successfully adapt to human (or mammalian) physiology.  There are undoubtedly more. 

 

Some we know about, some we probably don’t. 

 

Today’s report is a reminder that while the barriers to becoming a humanized flu are substantial, these avian viruses continue to re-invent themselves at a frantic pace, and their growing diversity only increases the odds that one will eventually hit the right genetic combination which could someday threaten mankind.

 

Study: H5 Clade 2.3.4.6 Receptor Binding

# 9460

 

 

Unlike in mammals, where influenza viruses generally produce a respiratory infection, influenza in birds is a gastrointestinal malady. The virus attaches to - and replicates in – the avian gut,  and is spread primarily through infected droppings.

 

As you might imagine, avian flu viruses are well adapted to attack the kind of cells found within the avian intestinal tract; α2,3-linked sialic acid  avian receptor cells.

 

Humans, and many (but not all) mammals have very few α2,3 receptor cells in their upper airway (but do have some deep in the lungs), making it difficult for avian flu viruses to easily attach to, and infect, non-avian species. 

 

When they do jump to humans, it usually results in a serious deep lung infection (pneumonia).

Human, or mammalian adapted flu viruses bind preferentially to a different type of cell - α2,6 receptor cells -  which are abundant in their upper respiratory systems. They are also adapted to replicate in the 5 to 10 degree cooler environment of the upper airway, compared to the intestinal tract of birds.

For an avian influenza virus to successfully jump species and to become a human pandemic threat, these receptor binding and temperature tolerance issues are believed to be two of the biggest hurdles.  There are likely others, but these two appear to top the list.

 

As avian viruses jump (even tentatively) to other species, it gives them a chance to produce host adaptations;  mutations that favor survival in their new environment. The more jumps, the more opportunities the virus has (through trial and error)  to `figure out’  what evolutionary changes are needed to make the new species a suitable host.

 

Viruses also change slowly through antigenic drift, even in their native hosts, and can abruptly change through antigenic shift – or reassortment.  Shift occurs when two flu viruses inhabit the same host at the same time, swap genetic material, and produce a `hybrid’ strain.  

Birds, swine, humans . . .  in fact almost any flu susceptible species – can act as a mixing vessel.  While pandemic viruses are rare, as any virologist will tell you . . . Shift happens.

 

While we are justifiably concerned over the recently emerged H7N9 virus given its track record over the past couple of years, the avian flu virus with the longest resume and greatest diversity is H5N1 and its recently emerged cousins; H5N8, H5N6, H5N3.  This virus has been around for 18 years, and has gone from a single clade discovered in 1996 to a diverse, and growing constellation of clades, sub-clades, and variants within sub-clades.

 

The following chart from the World Health Organization hints at just how much diversity the virus acquired over its first 15 years..

(click to load larger image)  (Note: Chart only goes through 2011)

 

Until a year or so ago, most H5N1 clades were classified by 3 digit identifiers, such a clade 2.3.4.

But in 2013, researchers reported on Novel Variants of Clade 2.3.4 Highly Pathogenic Avian Influenza A(H5N1) Viruses, China, and suggested that `these groups should be assigned new fourth-order clades of 2.3.4.4, 2.3.4.5, and 2.3.4.6 to reflect the wide divergence of clade 2.3.4 viruses.’

 

In short order, we saw the emergence of several new H5 subtypes (through reassortment), all carrying the newly identified H5 clade 2.3.4.6 HA gene segment, including the recent high flying H5N8 and H5N6 subtypes. The graphic below (produced before H5N8 showed up in Europe and North America) illustrates their recent geographic spread in Asia comes from the November FAO-EMPRES Report On The Emergence And Threat Of H5N6).

 

While there are a lot of H5 clades out there, and more will invariably appear, right now clade 2.3.4.6 is making a lot of noise.   So the open access study, published this week in the Journal Veterinary Research, that looks at the receptor binding qualities of this new clade is of particular interest.

 

While many will want to read the entire report, I’ve excepted some highlights below.

 

In short, they determined that this new clade binds to both avian α2,3  and mammalian α2,6 receptor cells, and that at least one (of 4 tested) strains replicated well, and transmitted efficiently, in test guinea pigs.

 

Novel H5 clade 2.3.4.6 viruses with both α-2,3 and α-2,6 receptor binding properties may pose a pandemic threat

Qunhui Li¹, Xuan Wang¹, Min Gu¹², Jie Zhu¹, Xiaoli Hao¹, Zhao Gao¹, Zhongtao Sun¹, Jiao Hu¹², Shunlin Hu¹², Xiaoquan Wang¹², Xiaowen Liu¹² and Xiufan Liu^12*

Abstract

The emerging H5 clade 2.3.4.6 viruses of different NA subtypes have been detected in different domestic poultry in China. We evaluated the receptor binding property and transmissibility of four novel H5 clade 2.3.4.6 subtype highly pathogenic avian influenza viruses. The results show that these viruses bound to both avian-type (α-2,3) and human-type (α-2,6) receptors. Furthermore, we found that one of these viruses, GS/EC/1112/11, not only replicated but also transmitted efficiently in guinea pigs. Therefore, such novel H5 subtype viruses have the potential of a pandemic threat.

<SNIP>

Discussion

Historically, changes in the receptor binding protein of influenza virus, HA, have been implicated in the initiation of a pandemic. It has been established for the H1N1 (1918), H2N2 (1957) and H3N2 (1968) pandemic viruses that a change in HA protein from a preference for α-2,3-linked sialic acids (avian receptor) to a preference for α-2,6-linked sialic acids (human receptor) is a prerequisite for efficient transmission of avian viruses to humans [10].

H5 HPAIV pose a serious pandemic threat due to their virulence and high mortality in humans, and their increasingly expanding host reservoir and significant ongoing evolution could enhance their human-to-human transmissibility. Recently, novel clade 2.3.4.6 H5 HPAIV with various NA subtypes (H5N1, H5N2, H5N6, and H5N8) were reported in Eastern China and South Korea [2]-[7],[9],[15].

Here, we evaluated their receptor specificity and transmission in guinea pigs. The results show that the viruses bound to both avian-type (α-2,3) and human-type (α-2,6) receptors. In humans, the α-2,6 receptor is expressed mainly in the upper airway, while the α-2,3 receptor is expressed in alveoli and the terminal bronchiole [16].

A virus with good affinity to both α-2,3 and α-2,6 receptors may especially be harmful, as it could infect efficiently via its binding to α-2,6 receptors in the upper airway and simultaneously cause severe infection in the lung via its binding to α-2,3 receptors. And this hypothesis is supported by the fact that one of the two well-characterized HA genes from the H1N1 1918 pandemic virus binds efficiently to both α-2,3 and α-2,6 receptors [17]. In addition, previous studies showed that the human-infecting novel H7N9 and the latest reassortant H10N8 avian influenza viruses yet have substantial affinity to both avian-type (α-2,3) and human-type (α-2,6) receptors [18],[19].

Sequence analysis showed that novel H5 (HPAIV) clade 2.3.4.6 simultaneously carry a T160A mutation which results in the lack of an oligosaccharide side chain at 158–160 of HA, and it is critical for the H5 subtype influenza viruses tested to bind to human-like receptors and to transmit among a mammalian host [20],[21]. Whether this T160A variation affects the receptor-binding property deserves further investigation.

Previous studies showed that some H5 subtype influenza viruses can transmit efficiently in guinea pigs [21]. In this study, we also found that one of these viruses, GS/EC/1112/11, not only replicated but also transmitted efficiently in guinea pigs. These findings emphasize that continued circulation of these viruses may pose health threats for humans. Therefore, we need to intensify our effort to detect such viruses as early as possible.

(Continue . . .. )

 

 

Although there are likely other inhibiting factors stopping this H5 clade 2.3.4.6 strain (and others) from sparking a pandemic, this dual binding ability would appear to move this particular clade a little closer towards it becoming a potential global health threat.  

 

That said, it should be noted that in 2013 we saw a similar finding with the H7N9 virus (see NEJM Journal Watch: Characteristics of H7N9), but that virus still has not displayed the ability to spread efficiently from human-to-human.

Despite our continual gains in knowledge regarding influenza viruses, we obviously don’t know all of the factors involved in turning an avian influenza virus into a `humanized’ one.  But studies like this one may help us recognize an impending threat, and give us enough warning time to prepare our defenses (i.e. vaccines, antivirals, etc.).

For more on the evolution of H5 and H7 viruses, you might wish to revisit:

 

Nature Comms: Host Adaptation Of Avian Influenza Viruses

EID Journal: Potential Human Adaptation Mutation of Influenza A(H5N1) Virus, Canada

PLoS: Human-Type H5N1 Receptor Binding In Egypt

TSRI: H7N9 Virus Still Binds Preferentially to Avian Receptors

Binding of H7N9 to Avian Receptors

Credit: Rui Xu, The Scripps Research Institute

 

# 8045

 

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.

(Continue . . . )

 

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.

(Continue . . . )

 

Nature: Receptor Binding Of H7N9

Flu Virus binding to Receptor Cells – Credit CDC

 

# 7909

 

For an influenza virus to infect a host, the virus must bind (attach) itself to the surface of a cell.  To do that influenza viruses have an RBS - Receptor Binding Site (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 host’s receptor cells.

 

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, most researchers believe it needs to a able to bind to the α2-6 receptor cell found in the upper airway (trachea).

 

We’ve seen studies over the summer that the emerging H7N9 virus in China – unlike the H5N1 virus – has shown signs of adapting to mammalian physiology (see Nature: Biological Features Of H7N9).   Among the findings:

 

• Unlike the H5N1 virus – which binds preferentially to avian receptor cells (a2,3-linked sialic acid) -  H7N9 binds to both the avian and human (a2,6-linked sialic acid) receptor cells.

• This dual receptor cell binding ability likely enhances the virus’s ability to transmit from birds to humans.

• The virus appears to replicate well in the lower human respiratory tract - but less well in the trachea – which may have helped to limit its ability to spread from human-to-human.

• Once infected, the virus often produces severe illness in humans, and patients tested showed increased serum levels of chemokines and cytokines, suggesting the possibility of infection inducing a `cytokine storm’.

• There appears to be little  or no community immunity to H7 viruses.

 

Today, we’ve another study appearing in the Journal Nature that looks at the ability of the H7N9 virus to bind to human receptor cells (in vitro), that finds the virus better adapted to human receptor cells than earlier H7N9 viruses, but perhaps still not quite ready for prime time.

 

 

Adaptation of novel H7N9 influenza A virus to human receptors

J. C. F. M. Dortmans, J. Dekkers, I. N. Ambepitiya Wickramasinghe, M. H. Verheije, P. J. M. Rottier, F. J. M. van Kuppeveld, E. de Vries & C. A. M. de Haan

ABSTRACT

The emergence of the novel H7N9 influenza A virus (IAV) has caused global concerns about the ability of this virus to spread between humans. Analysis of the receptor-binding properties of this virus using a recombinant protein approach in combination with fetuin-binding, glycan array and human tissue-binding assays demonstrates increased binding of H7 to both α2-6 and α2-8 sialosides as well as reduced binding to α2-3-linked SIAs compared to a closely related avian H7N9 virus from 2008. These differences could be attributed to substitutions Q226L and G186V. Analysis of the enzymatic activity of the neuraminidase N9 protein indicated a reduced sialidase activity, consistent with the reduced binding of H7 to α2-3 sialosides. However, the novel H7N9 virus still preferred binding to α2-3- over α2-6-linked SIAs and was not able to efficiently bind to epithelial cells of human trachea in contrast to seasonal IAV, consistent with its limited human-to-human transmission.

 

 

The entire study is open-access, and quite detailed regarding methods and materials.  The authors sum up their findings in the discussion:

 

The results indicate that, in comparison to avian H7N9 virus, the human H7N9 virus displays increased binding to α2-6 as well as α2-8 sialosides and reduced binding to α2-3-linked SIAs. Still, whereas all seasonal/pandemic IAVs bind more efficiently to α2-6- than to α2-3-linked sialosides, the human H7 protein binds more efficiently to α2-3- than α2-6-linked SIAs and is not able to efficiently bind to epithelial cells of human trachea. From these results we conclude that the human H7N9 virus has not (yet) adapted its HA protein to such an extent that it results in a receptor-binding profile similar to that of pandemic/seasonal IAV.

 

For more on the evaluation of the emerging H7N9 virus, you may wish to revisit:

 

Nature: H7N9 Pathogenesis and Transmissibility In Ferrets & Mice

Nature: Limited Airborne Transmission Of H7N9 Between Ferrets

Eurosurveillance: Genetic Analysis Of Novel H7N9 Virus

Nature: Biological Features Of H7N9

Credit CDC

 

 

# 7444

 

 

A study, published today in the Journal Nature, provides new insights into the H7N9 avian flu virus which emerged on the Chinese mainland earlier this spring, and suggests that should it return this winter, it could prove a far more formidable foe than than has H5N1 to date.

 

Chinese researchers, looking both at the virus in the laboratory, and at patient responses to infection, have concluded that this virus `poses a potentially high risk to humans.’.

 

Among their findings:

 

• Unlike the H5N1 virus – which binds preferentially to avian receptor cells (a2,3-linked sialic acid) -  H7N9 binds to both the avian and human (a2,6-linked sialic acid) receptor cells.

• This dual receptor cell binding ability likely enhances the virus’s ability to transmit from birds to humans.

• The virus appears to replicate well in the lower human respiratory tract - but less well in the trachea – which may have helped to limit its ability to spread from human-to-human.

• Once infected, the virus often produces severe illness in humans, and patients tested showed increased serum levels of chemokines and cytokines, suggesting the possibility of infection inducing a `cytokine storm’.

• There appears to be little  or no community immunity to H7 viruses.

 

 

First, a link to the letter in Nature (the abstract is available, but the whole letter is behind a pay wall). Given the barebones nature of the abstract, I’ll return with a little more background on some of their findings.

 

Biological features of novel avian influenza A (H7N9) virus

Jiangfang Zhou1*,DayanWang1*,RongbaoGao1*, Baihui Zhao2*, Jingdong Song1,XianQi3 ,Yanjun Zhang4, Yonglin Shi 5, LeiYang1, Wenfei Zhu1, Tian Bai 1,KunQin1, Yu Lan1, Shumei Zou1, JunfengGuo1, JieDong1 , LiboDong1 ,Ye Zhang1, HejiangWei 1, Xiaodan Li 1, Jian Lu1 , Liqi Liu1 , Xiang Zhao1, Xiyan Li 1, Weijuan Huang1, LeyingWen1 ,HongBo1 , Li Xin1, Yongkun Chen1 , Cuilin Xu1, Yuquan Pei 6,YueYang6 , Xiaodong Zhang6, ShiwenWang1,  Zijian Feng7 , JunHan7 ,Weizhong Yang7, George F. Gao7 , GuizhenWu1 ,Dexin Li 1, Yu Wang7 & Yuelong Shu1

 

 

Highlighting a few points raised by this study.

 

The authors note that H7N9:`. . .can invade epithelial cells in the human lower respiratory tract and type II pneumonocytes in alveoli . . ‘.

 

Pneumocytes (aka pneumonocytes) are a collective term for the two types of cells lining the alveoli (the air sacs) in the lung; Type I and Type II pneumocytes.

 

• Type I pneumocytes are responsible for the gas exchange (02 and C02) between the lungs and the blood stream.  Type I pneumocytes are easily damaged and cannot reproduce themselves.

• Type II pneumocytes are responsible for the production of surfactant, which reduces the surface tension of pulmonary fluids and contributes to the elasticity of the lungs.  

• Type II pneumocytes are able to replicate in the alveoli and can create new Type I pneumocytes.

 

A loss of type II pneumocytes can severely degrade the lungs ability to fight off an infection, and to repair damaged tissue. Earlier studies have demonstrated tropism for, and destruction of, type II pneumocytes by the avian H5N1 virus.

 

While still only partially understood, the idea behind a `cytokine storm’ is that the host’s immune system goes into overdrive, producing excessive levels of cytokines that can provoke damaging inflammation in the lungs.

 

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.

 

You can find more on this theory in these earlier posts:

 

Study: Calming The Cytokine Storm

Cytokine Storm Warnings

The Baskin Influenza Pathogenesis Study

Pt. 1               Pt. 2             Pt. 3

 

Another finding (across all age groups tested) was a lack of pre-existing immunity to the H7N9 virus, and that the current seasonal vaccine conveyed absolutely no protection.

 

As we’ve discussed earlier, while work is underway on creating seed strains for an H7N9 vaccine, getting one through the testing and manufacturing process and into the arms of hundreds of millions of people, is unlikely to happen in the near term (see JAMA: Challenges Of Producing An Effective & Timely H7N9 Vaccine).

 

For now, the saving grace with this virus is its apparent inability to spread efficiently from human-to-human. But should that change, the world could find itself facing a particularly nasty pandemic threat.

MIT: Two Avian Flu Receptor Cell Binding Studies

 

 

# 7370

 

We’ve a pair of avian flu studies, published today in the online journal Cell, that look at the current ability of both the H7N9 and H5N1 viruses to bind to human receptor cells.

 

While there may be other factors at play, the primary barrier that prevents these viruses from sparking a pandemic appears to be their preferential binding to avian receptor cells.

 

We’ve discussed receptor binding often in the past (see Study: Dual Receptor Binding H5N1 Viruses In China & PLoS: Human-Type H5N1 Receptor Binding In Egypt) but to review:

 

Flu Virus binding to Receptor Cells – Credit CDC

 

Human adapted influenza viruses have an RBS - Receptor Binding Site (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, most researchers believe it needs to a able to bind to the a 2,6 receptor cell.

 

The $64 question that the research team lead by Ram Sasisekharan, the Alfred H. Caspary Professor of Biological Engineering at MIT, have endeavored to answer is: what type - and how many - changes would these viruses need in order to become more transmissible in humans?

And the authors suggest, it’s probably not a lot.

 

Particularly with the H7N9 virus. 

 

Quick links to the abstracts to these two studies (both studies are, alas, behind pay walls), and then a look at the press release, that describes their findings.

 

Glycan Receptor Binding of the Influenza A Virus H7N9 Hemagglutinin

Cell, 06 June 2013
Copyright © 2013 Elsevier Inc. All rights reserved.
10.1016/j.cell.2013.05.034

Authors

Kannan Tharakaraman, Akila Jayaraman, Rahul Raman, Karthik Viswanathan, Nathan W. Stebbins, David Johnson, Zachary Shriver, V. Sasisekharan, Ram Sasisekharan

Highlights

• The hemagglutinin of H7N9 virus does not efficiently bind human receptors
• A single residue change in receptor binding site increases binding to human receptors
• Mutations on hemagglutinin may reduce the effectiveness of current H7 vaccines

(Continue . . . )

 

 

 

Structural Determinants for Naturally Evolving H5N1 Hemagglutinin to Switch Its Receptor Specificity

 

Cell, 06 June 2013
Copyright © 2013 Elsevier Inc. All rights reserved.
10.1016/j.cell.2013.05.035 

Authors

Kannan Tharakaraman, Rahul Raman, Karthik Viswanathan, Nathan W. Stebbins, Akila Jayaraman, Arvind Krishnan, V. Sasisekharan, Ram Sasisekharan

Highlights

• Hallmark mutations do not switch receptor preference of recent H5 strains
• Structural comparison of H5 and H2 hemagglutinin receptor complexes
• Determination of key H5Nl receptor-binding features needed for quantitative switch
• Recent strains may require a single base pair change to switch receptor preference

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While the full text of the articles are behind a pay wall, we do have a press release from MIT that tells us, in general terms, what these studies found. A few excerpts below, but follow the link to read it in its entirety.

 

 

Keeping an eye on bird flu

June 6, 2013

MIT studies of two influenza viruses reveal genetic mutations that could result in pandemic flu.

Anne Trafton, MIT News Office

 

(EXCERPTS)

New research from MIT shows that two recently emerged bird flu strains, which do not spread easily now, could become much more infectious with just one or a few genetic mutations.

 

The studies, which focused on the H5N1 and H7N9 flu strains, should help public health officials monitor evolving flu viruses for potential human-to-human transmission. They could also guide the development of new vaccines, says Ram Sasisekharan, the Alfred H. Caspary Professor of Biological Engineering and senior author of two papers appearing in the June 6 online edition of the journal Cell.

 

<SNIP>

 

H5N1

In the new Cell paper, the MIT team studied the structure of HA proteins from hundreds of H5N1 strains and identified three HA regions where one or two mutations would enable the HA to bind efficiently to human receptors. Most of these regions affect the base of the receptor-binding site.

 

The researchers also found that H5N1 has been evolving rapidly since 2005, but none of the current strains have all of the mutations needed to spread from human to human. However, the researchers found one strain that needs only a single amino-acid switch to become highly infectious, and several others that need only two. “There are multiple different ways that this can happen,” says Sasisekharan, who is also a member of MIT’s Koch Institute for Integrative Cancer Research.

 

Furthermore, because of all of the viral evolution that has occurred since 2005, the H5N1 vaccines that governments have stockpiled would probably no longer be effective, Sasisekharan says. “There is cause for concern,” he says. “Yet these findings open opportunities to make sure that some of these newer strains do become part of the stockpiling, because they are closer to human adaptation.”

 

H7N9

 

H7N9 has infected at least 132 people this year, mostly in China, and there have been 37 deaths, according to the World Health Organization — a lower fatality rate than that of the H5N1 virus.

The MIT researchers found that although the current circulating forms of H7N9 bind weakly to human receptors, a change in just one amino acid would dramatically increase the HA protein’s binding strength. “It was not a marginal increase; we saw a pretty significant increase in receptor binding,” Sasisekharan says.

 

“Our research provides insights to help keep track of potentially important mutations so that proactive steps can be taken to be better prepared against dangerous viruses.”

(Continue . . . )

 

 

Whether any avian influenza strain can make the right changes, and become a human pandemic strain, remains a mystery.

 

Yesterday, in a NEJM Perspective, David M. Morens, M.D., Jeffery K. Taubenberger, M.D., Ph.D., and Anthony S. Fauci, M.D. wrestled with this problem in:

 

Pandemic Influenza Viruses — Hoping for the Road Not Taken

This  remains one of the great debates in influenza science - and the question will likely only be settled after one finally does.

Nature: Receptor For NCoV Found

Photo Credit NIAID

 

# 7004

 

A fairly technical report appears in the Journal Nature  today - produced by research teams in both Europe and Saudi Arabia - that establishes the mechanism by which the novel Coronavirus NCoV (here called hCoV-EMC) binds to, and infects, mammalian cells.

 

They found this novel coronavirus uses a well known cell surface protein called dipeptidyl peptidase 4 (DPP4) to enter and infect human cells. 

 

This DPP4 cell surface protein (also called CD26) is evolutionarily conserved in other species, including bats (suspected of being potential species), non-human primates, and other animals – all of which suggests that this virus might be able to infect a wide range of hosts.

 

Working in vitro with Vero & COS-7 cells (African Green Monkey kidneys), Huh-7 (human hepato-carcinoma) and kidney cells of the P. pipistrellus bat, researchers found how hCoV-EMC’s receptor-binding domain latched onto cells. 

 

Using protein-specific antibodies, they were able to block specific receptors, systematically narrowing the field of possible attachment sites.

 

When DPP4 proteins were blocked, the virus was no longer able to attach to cells and cause infection. A discovery that could potentially lead to some specific treatment for this virus down the line.

 

These are, of course, early days.  And we still know very little about the origin – and the potential – of this virus.

 

The researchers point out that (in humans) DPP4 is primarily expressed by epithelial cells in the in kidney, small intestine, liver and prostate. They also observed that DPP4 is expressed by non-ciliated bronchial epithelial cells of the respiratory tract.

 

Locations consistent with the clinical picture of infection we’ve seen over the past year, that has often included both pneumonia and renal failure.

 

Declan Butler at Nature has far more on all of this, after which you’ll find a link to the study.

 

Receptor for new coronavirus found

Virus might have many animal reservoirs.

Declan Butler 13 March 2013

 

 

And the study’s abstract can be found at:

 

Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC

V. Stalin Raj, Huihui Mou, Saskia L. Smits, Dick H. W. Dekkers, Marcel A. Müller, Ronald Dijkman, Doreen Muth, Jeroen A. A. Demmers, Ali Zaki, Ron A. M. Fouchier, Volker Thiel, Christian Drosten, Peter J. M. Rottier, Albert D. M. E. Osterhaus, Berend Jan Bosch & Bart L. Haagmans