For a ubiquitous, low pathogenic, and relatively innocuous avian flu virus - one that rarely infects, and usually only mildly sickens humans - we spend an awful lot of time looking at, and trying to analyze, LPAI H9N2.
Where H9N2 shines is in its ability to reassort with other novel flu viruses, frequently lending its internal genes to some of the most dangerous avian flu viruses (H5N1, H7N9, H10N8) on the planet. A few (of dozens) of past studies include:
H9N2's promiscuity has helped to create a diverse and growing array of H5 and H7 viruses, some (even of the same subtype) being more pathogenic in humans than others (see Differences In Virulence Between Closely Related H5N1 Strains).
H9N2 continues to spread globally, having expanded its range to both the Middle East and Africa over the past decade.
This spread, and continual evolution of H9N2 - often aided and abetted by the use of older, less effective poultry vaccines (see J. Virus Erad.: Ineffective Control Of LPAI H9N2 By Inactivated Poultry Vaccines - China) - provides more opportunities for H9N2 to encounter, and reassort with, new influenza viruses.
The Asian avian H5N6 virus is a novel avian flu virus with a far more virulent track record in humans, although it has yet to develop the ability to transmit efficiently from human-to-human. So far there are only 53 known human infections, 52 of which have occurred in Mainland China.
Not all avian H5N6 viruses are able to infect, or sicken, humans (see Nature Sci Rpts: H5N6 Viruses Exhibit Varying Pathogenicity & Transmissibility In Mammals). But several subclades can, and the virus continues to evolve, primarily through reassortment.
Both viruses were of different subclades (188.8.131.52h & 184.108.40.206b), were the product of recent (and different) ressortments, and showed worrisome mutations which could increase their threat.
Given the recent increased level of H5N6 activity in China, this avian flu virus is suddenly back on everyone's radar (see CDC Adds A New H5N6 Avian Flu Virus To IRAT List).
Today we have a new study, published in PloS Pathogens, that looks at the apparent impact of H9N2's matrix protein 1 (M1) gene on H5N6's ability to infect mammals, including humans.
H9N2 virus-derived M1 protein promotes H5N6 virus release in mammalian cells: Mechanism of avian influenza virus inter-species infection in humans
Fangtao Li, Jiyu Liu, Jizhe Yang, Haoran Sun, Zhimin Jiang, Chenxi Wang, Xin Zhang, Yinghui Yu, Chuankuo Zhao, Juan Pu, Yipeng Sun, Kin-Chow Chang, Jinhua Liu , Honglei Sun
Published: December 3, 2021 https://doi.org/10.1371/journal.ppat.1010098
H9N2 AIVs are a major threat to human public health by acting as donors of viral genes through reassortment with co-circulating influenza viruses. Here, we demonstrated that H9N2 virus-derived M1, but not H5N1 virus-derived M1, enhances interaction with human host factor GNB1, to promote M1 transport to the cell membrane which, in turn, facilitates the interaction between M1 and HA proteins, ultimately improving viral assembly and release. Our results suggest that H9N2 virus-derived M1 protein, along with surface HA, is key to increased incidence of H5N6 influenza virus infection in humans.
While it may never happen - or it may take years before HPAI H5N6 evolves enough to pose a legitimate public health threat - another pandemic is considered inevitable (see PNAS Research: Intensity and Frequency of Extreme Novel Epidemics), and it could easily be worse than COVID.
Which is why we should be preparing seriously now, lest we risk being caught flat footed and unprepared.