Credit CDC
#17,878
A dozen years ago it was widely held that all influenza A viruses originated in avian species, and that all known subtypes were the product of 16 different hemagglutinin (H1 - H16) and 9 different neuraminidase (N1 - N9) surface proteins.
But over time, evidence - and our view of how things work - have a way of changing.
Last year geneticists presented Evidence for an aquatic origin of influenza virus and the order Articulavirales, predating the emergence of birds by hundreds of millions of years.
While it remains more theory than fact, it reminds us that facts often have a `limited shelf life', and what we say with confidence today is always subject to change.
Researchers also described its neuraminidase (NA) gene as `highly divergent from all known influenza NAs'.
In 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.
Although unlikely, one plausible scenario would involve the reassortment of a bat and a mammalian virus in an intermediate host, such as a pig. For the next two years only novel `bat specific' (H17 & H18) flu viruses were detected in bats, suggesting a wide gap between human and bat flu.
Things became less certain in 2015 when PLoS One published Serological Evidence of Influenza A Viruses in Frugivorous Bats from Africa, which detected serological evidence of prior H9 influenza infection in roughly 30% of bats examined in Ghana.
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's Back To The Bat Cave: More Influenza In Bats, we looked at a study that found that Bat lung epithelial cells were more permissive to avian rather than human viruses which suggest that bats could have a contributory role in the ecology of avian influenza viruses.
Also in 2018, In J. Virology: Isolation & Characterization of a Distinct Influenza A virus from Egyptian Bats, we saw a study that 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.
Fast forward to 2023 and we saw two additional studies of note:
In Preprint: The Bat-borne Influenza A Virus H9N2 Exhibits a Set of Unexpected Pre-pandemic Features published last May in Nature Portfolio, found 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
And while it wasn't found in a bat, in Emerg. Microb & Inf: Genetic Characterization of a New Candidate Hemagglutinin Subtype of Influenza A Viruses researchers described `. . . genomic evidence for a new candidate HA subtype, nominally H19, with a large genetic distance to all previously described AIV subtypes, derived from a cloacal swab sample of a Common Pochard (Aythya ferina) in Kazakhstan, in 2008.
All of which brings us to a new research report (that shares some authors with the H19 study above) that asks (and tries to answer) the question; did avian H9 originate from a bat source?
Spoiler Alert: (probably not, but . . . ) that doesn't change the fact that there is a mammalian adapted H9 influenza virus circulating in bats, and that has potential public health implications down the line.
I've only posted the Abstract and some excerpts, so follow the link to read it in its entirety. I'll have a postscript after the break.
Kobey Karamendin Aidyn Kydyrmanov Sasan Fereidouni
Influenza A viruses are important pathogens that can cause diseases with high mortality in humans, animals, and birds; and wild birds are considered the primary reservoir of all subtypes in nature. After discovering the H9 influenza A viruses in bats, questions arose about their potential to serve as an additional natural reservoir and about the priority of the viral origin: Did the virus initially circulate in bats and then transmit to birds or vice versa?Influenza A viruses of the H9 subtype are of particular interest because fatal infections of humans caused by H5, H7, and H10 influenza viruses contained RNA segments from H9 viruses. Recently, a novel subtype of influenza A virus (H19) was reported and it was closely related to the H9 bat influenza A virus by its hemagglutinin structure. The genome of novel H19 has revealed a mixed characteristic genomic signature of both avian and bat influenza viruses. The time to most recent common ancestor (TMRCA) estimates have shown that the divergence time between the bat and avian H9-similar influenza virus occurred approximately at the end of the XVIII century.This article discusses the evolution and possible origin of influenza viruses of the H9 subtype isolated from bats and birds. The obtained data, along with the known data, suggest that the primary reservoir of the H9 influenza virus is wild birds, from which the virus was transmitted to bats.
We hypothesize that the novel H19 could be a descendant of an intermediate influenza virus that was in the transition stage of spillover from avian to bat hosts.
Discussion
The H9 subtype is known for its broad host range, including birds, mammals, and humans, and it is well-established that reassortment between isolates from different host species can generate viruses with pandemic potential (16). Due to the high host adaptability of this subtype, it possessed substantial potential to be transmitted to a new bat host. Obviously, a separate mammalian lineage of the H9 influenza A virus has emerged in bat populations.
Interestingly, this H9 subtype lineage emerged in bats, and there is no evidence of similar events in human or pig populations, although it may potentially happen in the future. Extensive circulation of the bat lineage was serologically confirmed by the detection of neutralizing antibodies to H9 in several bat populations in Africa (5). The adaptation process in bats did not affect RBS as nearly all key genetic signature sequences retained avian features. It has been shown that although bats are resistant to avian H9 viruses, they are susceptible to specific bat H9 isolates (17).
The Caspian region is an important place where many wild bird migration routes intersect and different viral lineages and genotypes may potentially mix. In this region, subtypes of influenza A virus H14 (18) and H16 (19) were first discovered and reassortant American lineage H11 (20) and a novel paramyxovirus APMV-20 (21) were first identified. It is possible that mixed avian-bat viruses, such as H19, circulate in Africa, where H9 has been isolated from bats (5, 6), and spread to other places by migrating birds. A case of transmission of the H5 virus from Africa across the Caspian Sea by flamingo was previously described (22).
We assume that bat H9 viruses originated from avian H9 and the new avian H19 subtype could potentially be a descendant of an ancestor virus that further diverged into two lineages—bat and avian.
If we try to answer the question from the title of the article “Has avian influenza virus H9 originated from a bat source?,” based on the findings obtained in this study and available data (5, 6), we are inclined to hypothesize the opposite, that the H9 bat influenza virus originated from an avian reservoir.
With the increasing infection of humans with H9N2 in Asia, a major concern arises that this subtype may be the cause of the next worldwide pandemic, although no human-to-human transmission has yet been reported (4, 23). Therefore, regular monitoring of circulation and evolution of the H9 subtype viruses in animal and human populations have great importance in ensuring preparedness for adverse pandemic scenarios.
While likely highly under-reported, the number of human H9N2 cases reported in China (see chart below) continues to rise. In January 6th's CDTR, the ECDC reported:
As of 3 January 2024, and since 1998, a total of 130 laboratory-confirmed cases of human infection with avian influenza A(H9N2) viruses, including two deaths, have been reported in eight countries: China (117), Egypt (4), Bangladesh (3), Cambodia (2), Oman (1), Pakistan (1), India (1) and Senegal (1). Most of the cases were children with mild disease.
While perhaps not the most dangerous virus on our watch list, H9N2 is arguably the most versatile. All of which makes it very much worthy of our attention.
