Tuesday, May 30, 2023

Preprint: The Bat-borne Influenza A Virus H9N2 Exhibits a Set of Unexpected Pre-pandemic Features

Flu Virus binding to Receptor Cells – Credit CDC


In 2012 scientists from the U.S. CDC and the Universidad del Valle in Guatemala City announced the first discovery of a bat-borne influenza A (H17) virus collected from little yellow-shouldered bats (Sturnira lilium) captured at two locations in Guatemala (see A New Flu Comes Up To Bat).

While a remarkable finding, researchers were unable to propagate this virus in cell cultures, suggesting it was a long way from being able to pose a threat to humans.

Two years later (2013), another new subtype (H18N11) was identified, again in South American Bats (see PLoS Pathogens: New World Bats Harbor Diverse Flu Strains), leading to speculation that these mammalian-adapted flu viruses might someday jump to other species – including man.

For the next couple of years only novel `bat specific' (H17 & H18) flu subtypes were detected in bats, suggesting a wide gulf between human and bat flu.

In 2015 PLoS One published Serological Evidence of Influenza A Viruses in Frugivorous Bats from Africa - which described serological evidence of prior H9 influenza infection in bats tested in Ghana - raising new questions about the range of flu viruses carried by bats.

The author's wrote:
Preliminary results indicate serological evidence against avian influenza subtype H9 in about 30% of the animals screened, with low-level cross-reactivity to phylogenetically closely related subtypes H8 and H12.
To our knowledge, this is the first report of serological evidence of influenza A viruses other than H17 and H18 in bats. As avian influenza subtype H9 is associated with human infections, the implications of our findings from a public health context remain to be investigated.

In 2018 (see J. Virology: Isolation & Characterization of a Distinct Influenza A virus from Egyptian Bats) a study described the isolation and characterization of a genetically distinct Influenza A H9-like virus from Egyptian fruit bats which already had the ability to replicate in the lungs of experimentally infected mice.

The authors wrote: 

Through surveillance, we isolated and characterized an influenza A virus from Egyptian fruit bats. This virus had affinity to avian-like receptors but was also able to infect mice. Our findings indicate that bats may harbor a diversity of influenza A viruses. Such viruses may have the potential to cross the species barrier to infect other species including domestic birds and mammals and possibly humans.

The fact that the virus they isolated was similar to LPAI H9N2 - a promiscuous avian virus that is already ubiquitous in poultry and wild birds, and has spilled over into humans scores of times (see FluTrackers case list) - only increased concerns. 

Although most reported H9N2 human infections have been mild or moderate, in November of 2021 China reported a rare fatal outcome in a 39-year-old man from Qiandongnan Autonomous Prefecture, Guizhou Prefecture. 

While H9N2 may not be at the very top of our pandemic threats list, it is still regarded as having at least some pandemic potential (see CDC IRAT SCORE), and several candidate vaccines have been developed

All of which brings us to a new preprint, published last week in Nature Portfolio, which finds the bat-borne Old World H9N2 virus isolated in Egypt in 2017 already ticks a lot of the pre-pandemic boxes;

    • it readily infects and transmits incredibly well among ferrets
    • it replicates efficiently in human (explant) lung tissue
    • is able to escape human MxA (myxovirus resistance protein A)
    • there appears to be little pre-existing community immunity to H9 viruses 
I've only posted the abstract and a brief excerpt from the body of the report, so follow the link to read it in its entirety.  I'll have a brief postscript when you return. 
The bat-borne influenza A virus H9N2 exhibits a set of unexpected pre-pandemic features

Nico Halwe, Lea Hamberger, Julia Sehl-Ewert, Christin Mache, Jacob Schön, and 23 more

This work is licensed under a CC BY 4.0 License

          PDF Link 


An Old-World bat H9N2 influenza A virus (IAV) identified in Egypt exhibits high replication and transmission potential in ferrets, efficient infection of human lung explant cultures and marked escape from the antiviral activity of MxA. Together with low antigenic similarity to N2 of seasonal human strains, bat H9N2 meets key criteria for pre-pandemic IAVs.


Our study shows that the Old World bat H9N2 virus meets key characteristics of a pre pandemic IAV, including replication in and efficient transmission between ferrets, the ability to replicate efficiently in human lung explants and evasion from MxA-mediated restriction.  Intriguingly, bat H9N2 exhibits an immediate (at 1 dpe) and highly efficient transmission potential (100%) not previously observed in any avian-derived H9N2 isolate24 , which may also 7 allow for spread among and further adaptation to humans. 

Our data also suggests that bat H9N2 can suppress the expression of MxA, thereby overcoming this important restriction factor for zoonotic spill-over25 . This is in strong contrast to zoonotic H5N1 and H7N9 viruses of avian origin that are potently inhibited in hMxAtg/tg mice21. Given the ability of bat H9N2 to infect turkey hatchlings, introduction of bat H9N2 into poultry farms and reassortment with avian IAV cannot  be ruled out, necessitating increased attention and close monitoring of possible human spillover infections in Africa. 

A further prerequisite of pre-pandemic viruses is their antigenic novelty to the human immune system. Since the human population is presently exposed only to the currently-circulating H1N1 and H3N2 subtypes, a lack of humoral immunity to bat H9N2 is very likely. Indeed, our serological data demonstrates that seasonal influenza vaccines containing H1N1 and H3N2 do not elicit cross-reactive antibodies to the bat N2 protein, substantiating the general pre pandemic features of bat H9N2.

          (Continue . . . )

Were it easy for novel avian, swine, or bat influenza viruses to adapt to human physiology, we'd be hip deep in pandemic viruses all of the time. Fortunately, there are a number of `species barriers' that must be overcome, including (but not limited to):

A lot of novel flu viruses are able to overcome one or two of these obstacles, but only rarely do we see one circumvent all three.  While this hat-trick may not be all that is required to launch this bat-borne H9N2 virus on a world tour, it is an impressive start. 

Add in (at least avian) H9N2's track record of spilling over into pigs and other mammals, and its ability to reassort with other influenza viruses, and that makes this bat-borne H9N2 virus one worthy of our attention.