Thursday, November 02, 2017

Vet. Research: Synergistic AA Changes That Enhance Virulence Of H5N8 In Mice


Although it has racked up an impressive number of air miles in just under four years - carried by migrating birds from Asia to North America, Europe, the Middle East, and along the full length of the African Continent - HPAI H5N8 (unlike its cousins H5N1 & H5N6) has shown no signs of posing a threat to human health.
There are rumors - as yet unconfirmed - of the detection of H5N8 antibodies in exposed humans in Russia, and there were reports of H5N8 antibodies detected in Korean dogs in 2014, but so far H5N8 has not been linked to any human illness. 
Given its rapid global spread there is understandable interest in figuring out what changes this virus would need in order to pose a serious human health threat. While we know some of the genetic markers (amino acid changes) that signify (or suggest) mammalian adaptation, we certainly don't know all of them - or how they might complement each other. 

We've looked at a number of studies over the past year that suggest the virus might, over time, adapt better to mammals - including:
J. Virulence Editorial: HPAI H5N8 - Should We Be Worried?
J. Virulence : Altered Virulence Of (HPAI) H5N8 Reassortant Viruses In Mammalian Models

Study: Virulence Of HPAI H5N8 Enhanced By 2 Amino Acid Substitutions

J. Vet. Sci.: Experimental Canine Infection With Avian H5N8
Sci Rpts: H5N8 - Rapid Acquisition of Virulence Markers After Serial Passage In Mice

Despite all of this, the H5N8 virus has been remained reassuringly benign for humans.

We've another study to add to the list, published last week in Veterinary Research, that identifies a new (PB2 283M) mammalian virulence marker for H5 viruses (not just H5N8), and shows that when combined with another amino acid (AA) change (PB2 526R), produces high virulence in mice.
While parts of this lengthy open access study are fairly technical, the upshot here is researchers continue to find new combinations of amino acid changes - that were they to become fixed in the virus - could significantly elevate the threat from HPAI H5N8.
How likely these specific lab-created combinations would appear spontaneously in the wild, and manage to thrive, is impossible to predict. But knowing what changes signify increased risk might give us some advance warning should we start seeing them crop up in the wild.
At least that's the hope. Our track record in that regard hasn't been exactly encouraging.
Follow the link to read the full open-access report. I'll return with a postscript.

Synergistic effect of PB2 283M and 526R contributes to enhanced virulence of H5N8 influenza viruses in mice

Xiao Wang†, Sujuan Chen†, Dandan Wang, Xixin Zha, Siwen Zheng, Tao Qin, Wenjun MaEmail author,  Daxin PengEmail authorView ORCID ID profile and Xiufan Liu
Veterinary Research 201748:67

Published: 25 October 2017

Highly pathogenic avian influenza (HPAI) H5N8 virus has caused considerable economic losses to poultry industry and poses a great threat to public health. Our previous study revealed two genetically similar HPAI H5N8 viruses displaying completely different virulence in mice. However, the molecular basis for viral pathogenicity to mammals remains unknown.
Herein, we generated a series of reassortants between the two viruses and evaluated their virulence in mice. We demonstrated that 283M in PB2 is a new mammalian virulence marker for H5 viruses and that synergistic effect of amino acid residues 283M and 526R in PB2 is responsible for high virulence of the HPAI H5N8 virus.

Analysis of available PB2 sequences showed that PB2 283M is highly conserved among influenza A viruses, while PB2 526R presents in most of human H3N2 and H5N1 isolates. Further study confirmed that the residues 283M and 526R had similar impacts on an HPAI H5N1 virus, suggesting that influenza viruses with both residues may replicate well in mammalian hosts. Together, these results present new insights for synergistic effect of 283M and 526R in PB2 of H5 HPAI virus on virulence to mammalian host, furthering our understanding of the pathogenesis of influenza A virus.

Since H5N1 highly pathogenic avian influenza (HPAI) virus was first detected from sick goose in Guangdong province in China in 1996, the HPAI H5N1 virus has caused huge economic loss for poultry industry worldwide, and also infected more than 850 humans since 2003 with approximately 50% fatality rate [1], which has been considered as one of candidates to cause the next human pandemic [2, 3].
In late 2013 and early 2014, an HPAI H5N8 virus belonging to the clade of the A/goose/Guangdong/1/1996 lineage caused a large outbreak in domestic poultry in South Korea [4]. Subsequently, the HPAI H5N8 virus was detected in birds in Asian and European countries and outbreaks in domestic poultry caused by this virus have been reported in China, Japan, Germany, the United Kingdom and the United States during 2014–2016 [5, 6, 7, 8, 9]. Further spread of the HPAI H5N8 virus along the migratory route of wild birds is possible, and introduction into other countries could occur [10].
Although no human infection case of H5N8 avian influenza virus has been reported, human infections with the related clade H5N6 viruses have been reported in China [11]. Outbreaks of HPAI H5N8 virus have caused significant economic losses to the poultry industry, and more importantly, its potential threat to public health cannot be neglected.

Discussion (Excerpt)

Based on available influenza PB2 sequences, we show that PB2 283M is highly conserved among various subtypes of IAVs, while 526R is scarce in H3N2 avian influenza viruses, and in H1N1 and H7 viruses isolated from swine, avian or human. However, the percentage of PB2 526R in H3N2 and H5N1 human isolates is 89.2 and 30.0%, respectively. The fact implies that the virus with both 283M and 526R in the PB2 probably has more chance to infect and adapt to humans in nature.

In summary, we have demonstrated synergistic effect of amino acid residues 283M and 526R in the PB2 responsible for enhancing virulence of HPAI H5 viruses in mice. Importantly, residues 283M is highly conserved among various subtypes of IAVs, while residues 526R have been found in the most of human H3N2 viruses that cause human seasonal influenza epidemic, and in many H5N1 human isolates that have been considered to be one of candidates to cause next pandemic [3, 62], suggesting their importance in structure of polymerase and virulence to mammalian.
The synergistic effect of 283M and 526R in PB2 may enhance replication of an avian influenza virus in mammalian hosts. Therefore, it warrants attention to give an influenza virus that has the virulence markers during surveillance.
         (Continue . . . )

When H5N8 returned to Europe in the fall of 2016 after nearly a two year absence it brought with it new virulence, an expanded host range, and significant genetic changes (see EID Journal: Reassorted HPAI H5N8 Clade - Germany 2016). 
This reinvented virus - which previously had only made a brief appearance and had a minor impact in Europe - went on to produce the largest epizootic in European history.
According to the ECDC/EFSA Joint Report: Avian Influenza Overview Oct 2016–Aug 2017 report, between 19 October 2016 and 31 August 2017 (based on ADNS):
  • 1,197 H5 HPAI outbreaks were reported in poultry or captive birds in 20 MSs 1,188 A(H5N8), 8 A(H5N5) and 1 A(H5N6);
  • 1,470 H5 HPAI events were reported in wild birds in 23 MSs: 1,458 A(H5N8) HPAI and 12A(H5N5);
  • 65 H5 LPAI outbreaks were reported in poultry and/or captive birds in 4 MSs, and 1 H7 LPAI outbreak was reported in poultry in France
This newly evolved H5N8 virus not only spread faster and farther than any other HPAI virus on record - it had considerably greater impact on wild and migratory birds than any previous subtype we've seen (see Avian Flu: That Was Then . . This Is Now).
While none of this guarantees that H5N8 will someday evolve into a human health threat, the virus has shown a remarkable ability to adapt, thrive, and to surprise.
Which means we can't simply assume just because it hasn't . .  .  that it can't.

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