The global prevalence of PB2-627V in influenza A viruses
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While we've been closely watching various incarnations of HPAI make sporadic attempts at spilling over into humans for nearly 3 decades, we've been largely protected because avian flu viruses typically carry the PB2-E627 amino acid mutation, which is not fully compatible with human ANP32A/B proteins.
In 2016 Wendy Barclay et al. identified ANP32 as an important limiting factor in the replication of avian viruses in mammalian hosts (see Species difference in ANP32A underlies influenza A virus polymerase host restriction) along with the role of specific PB2 mutations:
The bottom line being, avian flu viruses don't replicate particularly well in human (or mammalian) hosts.
But, occasionally, we've seen avian viruses pick up a PB2-627K mutation - usually after infecting a mammal - which is associated with enhanced replication and pathogenicity in mammals.
Fortunately, this mutation attenuates its ability to replicate in birds, thereby limiting its ability to spread in the wild.
The authors reported that this PB2-627V mutation not only maintained viral fitness in poultry, it facilitated the aerosol transmission of AIVs between ferrets; raising concerns this mutation could go a long way in overcoming the `species barrier' between avian and mammalian-adapted influenza viruses.Also last summer, in Transboundary & Emerg. Dis.: H3 Avian Influenza Virus Isolated from China in 2021–2022 Showed the Emerging H3N8 Posed a Threat to Human Health, we learned this mutation turned up in a human infection with avian H3N8 in Hunan province.
The authors wrote:
The E627K mutation of PB2 is known to play a decisive role in the mammalian adaptation of AIVs [41, 42]. The A/Henan/4-10CNIC/2022(H3N8) virus contains the E627K mutation, whereas A/Changsha/1000/2022(H3N8) contains the E627V mutation, which has also been shown to increase the replication or virulence of AIVs in mammals [14, 34, 43]
More recently, in Vet. Research: E627V Mutation in PB2 Protein Promotes the Mammalian Adaptation of Novel H10N3 Avian Influenza Virus, we saw evidence that PB2-627V is becoming increasingly common in AIV poultry isolates in China.
All of which brings us to a new research article, published yesterday in the Journal of Virology, which calls for `PB2-627V be included as a molecular marker to assess the zoonotic risk of AIVs'.
An emerging PB2-627 polymorphism increases the zoonotic risk of avian influenza virus by overcoming ANP32 host restriction in mammalian and avian hosts
Authors: Yuxin Guo Sicheng Shu , Yong Zhou, Wenjing Peng, Zhimin Jiang, Yudong Li, Tian Li, Show All (21 Authors) , Juan Pu h pujuan@cau.edu.cn
ABSTRACT
Alterations in the PB2-627 domain of avian influenza virus (AIV) can potentially increase the risk of cross-host species infections in humans and mammals. Recently, there has been a rise in human cases of AIV infections without the presence of the known mammalian determinant PB2-E627K.
Here, we identified a variant, PB2-627V, which has evolved in poultry and has contributed to the increase in human AIV infections. By screening global PB2 sequences, we discovered a new independent cluster of PB2-627V that emerged in the 2010s, prevalent in avian, mammalian, and human AIV isolates, including those of H9N2, H7N9, H3N8, 2.3.4.4b H5N1, and other subtypes.
We functionally assessed its host adaptation, fitness, and transmissibility across three subtypes of AIVs (H9N2, H7N9, and H3N8) in different host models. PB2-627V combines the viral properties of avian-like PB2-627E and human-like PB2-627K, facilitating AIVs to efficiently infect and replicate in chickens and mice by utilizing both avian- and human-origin ANP32A proteins.
Importantly, PB2-627V promotes efficient transmission between ferrets through respiratory droplets. Deep sequencing of passaged chicken and transmitted ferret viral samples indicates that PB2-627V remains stable across the two host species and shows a high potential for long-term prevalence in avian species. Thus, the PB2-627V mutation in AIVs can stably transmit through poultry and can overcome the cross-species barrier to infect humans. Given the global prominence of AIVs, it will be prudent to monitor influenza viruses for the PB2-627V mutation as a potential marker for zoonotic spread.
IMPORTANCE
Avian influenza viruses (AIVs) are significant zoonotic pathogens. There is a rising trend of human cases of AIVs caused by a range of virus subtypes, including H9N2, H3N8, and H5N1 viruses. Thus, it is crucial to understand the underlying viral changes in AIVs that could result in zoonotic spread.
We identify mutation PB2-627V as an emerging viral factor that confers dual ability to the virus to infect and adapt to mammalian and avian hosts, and virus transmissibility in ferrets. The presence of PB2-627V in multiple subtypes of AIVs has the potential to cause public health risk. We therefore propose that PB2-627V be included as a molecular marker to assess the zoonotic risk of AIVs.
While global surveillance and reporting on sequences remains limited - and publication often lags by years - if this upward trend in PB2-627V continues, it could increase the zoonotic risk from a wide variety of avian flu subtypes (H3N8, H5N1, H5N5, H7N9, H9N2, etc.).
There are likely other genetic hurdles (e.g. Receptor binding) that avian flu viruses must overcome before they can pose a legitimate pandemic threat, but poor replication has long been viewed as a major barrier.
More proof, as if we needed, that Nature's laboratory is open 24/7 and we should expect to see more surprises along the way.
