PLoS One: Structural and Functional Studies of Influenza Virus A/H6 Hemagglutinin

Flu Virus binding to Receptor Cells – Credit CDC

 

#10,378

 

Although ubiquitous in birds, until a couple of years ago, avian H6 viruses as human health threats were essentially flying under the radar.  While implicated in the creation of H5N1 (see Hatta & Kawaoka, 2002), its history suggested that it posed little or no direct threat to human health – and after the return of H5N1 in 2003 – relatively little attention was paid to it

 

All that changed in May of 2013 when Taiwan health officials  – employing heightened surveillance due to the outbreak of  H7N9 on the Chinese mainland – stumbled across the first known human infection with an avian H6 virus (see Taiwan CDC Reports Human Infection With Avian H6N1)

The patient was described as a 20-year-old female who presented at local hospital with mild pneumonia on May 8th, was hospitalized and treated with oseltamivir, and who was released 3 days later.  None of 36 close contacts followed up on were found to be infected with the H6N1 virus.

Six months later, in Taiwan CDC: Epidemiological Analysis Of Human H6N1 Infection, researchers 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.”

 

Since then, we’ve seen a growing body of research emerge suggesting that H6 viruses in general – and H6N1 in particular – are possibly evolving towards a more human-adapted virus, and are therefore worthy of both our increased attention and surveillance.

 

• In TSRI: H10N8 and H6N1 Bind Poorly To Human Receptor Cells 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 and evolve isn’t complete enough to warrant complacency.
• Last May, 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. 
• Again in May, a study documented recent changes in the receptor binding characteristics of the H6N1 virus (see Adaptation of avian influenza A (H6N1) virus from avian to human receptor-binding preference).
• And just last month, another study that found traces of Influenza A(H6N1) Circulating In Dogs, Taiwan.

 

Before avian influenza viruses can pose a serious threat to human health they must acquire a number of mammalian adaptations.  Some we know about – like binding to human receptor cells and replicating at the lower temperatures found in mammalian airways – and others we don’t.

 

Arguably the most important step: the virus must be able to attach to the surface of cells in the respiratory tract, and in humans, that means binding to α2-6 receptor cells that are abundant in the upper airway (trachea).

 

Since avian flu viruses bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds, a series of amino acid changes are needed in its RBS (Receptor Binding Site) to allow it to attach to human receptor cells.  Some avian viruses can bind to both types of cells, although α2-6 binding is usually much weaker.

 

In the studies mentioned above there is growing evidence that the pendulum of binding preference in H6N1 may be swinging from avian to human receptors.  Today, we’ve another study that adds weight to those concerns. 

 

It’s a lengthy and highly technical report, and I would invite those so inclined to read it in its entirety at the link below.  I’ve only excerpted the abstract.

 

The bottom line, however, is they found that the Taiwan H6 HA has a slight preference for human receptors, and that it may represent an intermediate step towards a complete human adaptation.

 

Research Article

Structural and Functional Studies of Influenza Virus A/H6 Hemagglutinin

Fengyun Ni, Elena Kondrashkina, Qinghua Wang

Published: July 30, 2015

DOI: 10.1371/journal.pone.0134576  

Abstract

In June 2013, the first human infection by avian influenza A(H6N1) virus was reported in Taiwan. This incident raised the concern for possible human epidemics and pandemics from H6 viruses. In this study, we performed structural and functional investigation on the hemagglutinin (HA) proteins of the human-infecting A/Taiwan/2/2013(H6N1) (TW H6) virus and an avian A/chicken/Guangdong/S1311/2010(H6N6) (GD H6) virus that transmitted efficiently in guinea pigs.

Our results revealed that in the presence of HA₁ Q226, the triad of HA₁ S137, E190 and G228 in GD H6 HA allows the binding to both avian- and human-like receptors with a slight preference for avian receptors. Its conservation among the majority of H6 HAs provides an explanation for the broader host range of this subtype. Furthermore, the triad of N137, V190 and S228 in TW H6 HA may alleviate the requirement for a hydrophobic residue at HA₁ 226 of H2 and H3 HAs when binding to human-like receptors.

Consequently, TW H6 HA has a slight preference for human receptors, thus may represent an intermediate towards a complete human adaptation. Importantly, the triad observed in TW H6 HA is detected in 74% H6 viruses isolated from Taiwan in the past 14 years, suggesting an elevated threat of H6 viruses from this region to human health. The novel roles of the triad at HA₁ 137, 190 and 228 of H6 HA in binding to receptors revealed here may also be used by other HA subtypes to achieve human adaptation, which needs to be further tested in laboratory and closely monitored in field surveillance,

(Continue . . .)

 

The finding that 74% of the H6N1 samples isolated from Taiwan over the past 14 years now carry this N137/V190/S228 triad, which allows the binding to both avian- and human-like receptors, suggests that these H6 viruses may represent a growing threat to human health.

While there is no clear winner in the avian flu sweepstakes, the field continues to broaden with each passing year.  Where once we worried only about H5N1, over the past two years we’ve seen serious human infections with H7N9, H6N1, H5N6, and H10N8.   

While the odds of any one of these subtypes becoming a `humanized’  flu strain are likely pretty long, the more candidates you have, the greater the chances are that one will succeed. 

 

So we watch the evolutionary progress of viruses like H6N1 closely, in hopes that we’ll have some advance warning if it becomes a more tangible threat.