Recent Papers On The Zoonotic Potential of Bat-borne H9N2

Flu Virus binding to Receptor Cells – Credit CDC

#18,030

While the world is understandably focused on the spillover of HPAI H5N1 to cattle, this isn't the first time a novel avian flu virus has been found spreading in an unexpected mammalian host.  

Twelve years ago, the 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).

Two years later (2013), another new subtype (H18N11) was identified 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.

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:

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 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). 

In May of 2023 we looked at a preprint (The bat-borne influenza A virus H9N2 exhibits a set of unexpected pre-pandemic features), published in Nature Portfolio, which suggested the bat-borne Old World H9N2 virus isolated in Egypt in 2017 already ticked 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), which provides a potent & broad antiviral against many RNA viruses, including influenza A.  
• there appears to be little pre-existing community immunity to H9 viruses 

This study has now been updated and was published in Nature Communications this week under the title:

Bat-borne H9N2 influenza virus evades MxA restriction and exhibits efficient replication and transmission in ferrets

This week another paper was published in Nature Communications, one that has attached the names of some of the best known avian flu virologists in the world (Webster, Webby & Peiris).   

While lengthy and at times technical, you'll want to follow the link to read it in its entirety. 

Cross-species spill-over potential of the H9N2 bat influenza A virus

Rabeh El-Shesheny,John Franks, Ahmed Kandeil, Rebecca Badra, Jasmine Turner, Patrick Seiler, Bindumadhav M. Marathe, Trushar Jeevan, Lisa Kercher, Meng Hu, Yul Eum Sim, Kenrie P. Y. Hui, Michael C. W. Chan,Andrew J. Thompson, Pamela McKenzie, Elena A. Govorkova, Charles J. Russell, Peter Vogel, James C. Paulson, J. S. Malik Peiris, Robert G. Webster, Mohamed A. Ali, Ghazi Kayali & Richard J. Webby

Nature Communications volume 15, Article number: 3449 (2024) Cite this article

Abstract

In 2017, a novel influenza A virus (IAV) was isolated from an Egyptian fruit bat. In contrast to other bat influenza viruses, the virus was related to avian A(H9N2) viruses and was probably the result of a bird-to-bat transmission event. 

To determine the cross-species spill-over potential, we biologically characterize features of A/bat/Egypt/381OP/2017(H9N2). The virus has a pH inactivation profile and neuraminidase activity similar to those of human-adapted IAVs. 

Despite the virus having an avian virus–like preference for α2,3 sialic acid receptors, it is unable to replicate in male mallard ducks; however, it readily infects ex-vivo human respiratory cell cultures and replicates in the lungs of female mice. A/bat/Egypt/381OP/2017 replicates in the upper respiratory tract of experimentally-infected male ferrets featuring direct-contact and airborne transmission.

These data suggest that the bat A(H9N2) virus has features associated with increased risk to humans without a shift to a preference for α2,6 sialic acid receptors.

          (SNIP)

Discussion

The identification of the A(H17N10) and A(H18N11) viruses that are genotypically and phenotypically distinct from other influenza A viruses suggests that bats harbor their own lineages of virus. Although the origin of these viruses is unclear, the phylogenetic positioning of their internal genes at the base of influenza A genes, just downstream of the influenza A/B split1, could mean that the viruses have been in bats for a long time. Without definitive precursors, it has been difficult to assess the impact of bat adaptation of an influenza virus on the risk posed to humans. 

However, the identification of the A(H9N2)-like virus offers the possibility of investigating this impact. This virus has been in bats for a shorter period than the A(H17N10) and A(H18N11) viruses and is clearly derived from avian A(H9N2) viruses. The objective of this study was to examine the phenotypic properties of the bat A(H9N2) virus and compare it with their avian-origin counterparts.

(SNIP)

Our data indicate that the bat A(H9N2)-like virus has a mix of biologic properties, some typically associated with avian influenza viruses, some with human influenza viruses. This mix of phenotypes makes it difficult to assess the pandemic risk of the virus in relation to other zoonotic threats.

The capacity of the virus to transmit between ferrets and its HA stability profile do, however, indicate a certain level of zoonotic threat. Therefore, further investigating the abundance and nature of influenza viruses in bats and comparisons with other avian viruses with different levels of mammalian adaptations appears prudent.

          (Continue . . . ) 

While H9N2 (either avian or bat-borne) may seem pretty far down our list of pandemic concerns, we have an astonishingly bad track record of reading the tea leaves and predicting the next big public health threat.  

The H5N1 virus currently looms large, but the speed of viral evolution (particularly via reassortment) is such that we can easily be blindsided by a threat we never saw coming.

In the second half of the last century it was widely believed that - due to advances in modern medicine - that infectious diseases were largely conquered, and pandemics were a relic of the past.  Our going 40+ years between pandemics (1968 to 2009) - with both of them relatively mild -  only reinforced that idea. 

But the last interpandemic period was less than a decade (2010 to 2020), and COVID was severe enough to kill tens of millions around the globe. And now, a year after COVID was declared `over', we are facing a new potential threat with H5N1. 

Last fall, in BMJ Global: Historical Trends Demonstrate a Pattern of Increasingly Frequent & Severe Zoonotic Spillover Events, the authors suggested `. . . that the series of recent epidemics sparked by zoonotic spillover are not an aberration or random cluster, but follow a multi-decade trend in which spillover-driven epidemics have become both larger and more frequent.'

Which means that even if we are lucky enough that H5N1 fizzles, there is almost certainly another pandemic contender in the wings, waiting to begin its world tour.