#17,139
Among avian flu viruses, we are currently most concerned with the zoonotic threat of HPAI H5 - which is driving the largest, and most intense avian epizootic on record (see USDA/APHIS Snapshot: HPAI H5N1 In The United States) - but it is far from being the only avian flu virus on our watch list.
In addition to other clades of HPAI H5, we've seen large outbreaks of HPAI H7 viruses, including H7N9 which infected more than 1,500 people in China between 2013-2017, killing hundreds.
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| Credit FAO - Dec 5th 2017 Update |
While far less deadly, we've also seen scores of human infection with LPAI H9N2, along with scattered spillover of other avian viruses (e.g. H10N8, H3N8, H7N4, H7N2, etc.). It is likely that spillovers of avian and swine variant flu viruses into humans occur far more frequently than is reported, given the lack of surveillance and testing for novel flu viruses around the globe.
Not quite 10 years ago Taiwan's CDC Reported the 1st Human Infection With Avian H6N1 in a 20 year-old female who was hospitalized for pneumonia. The case might have gone undiagnosed were it not for the enhanced surveillance for H7N9, which had just broken out on the mainland.
In 2014 we learned that H6N1 had jumped to Taiwanese dogs (see Taiwan: Debating The Importance Of H6N1 In Dogs), while the following year - in EID Journal: Seropositivity For H6 Influenza Viruses In China - researchers reported on a small, but significant number of people in their survey who tested positive for H6 influenza antibodies (indicating previous exposure).
H6N6 viruses have also been reported in Chinese pigs (see Pathogenicity and transmission of a swine influenza A(H6N6) virus).
Also in 2015, in Study: Adaptation Of H6N1 From Avian To Human Receptor-Binding, we saw a report citing changes the authors suggest are slowly moving the H6N1 virus towards preferential binding to human receptor cells instead of avian receptor cells
In 2020's Nature: Evolution & Pathogenicity of H6 Avian Influenza Viruses, Southern China 2011-2017, we looked at H6's increasing adaptation to mammalian physiology, and again 6 weeks ago in Study: Influenza A (H6N6) Viruses Isolated from Chickens Replicate in Mice and Human lungs Without Prior Adaptation.
But since LPAI H6 viruses only rarely produce clinical illness in poultry, and are not legally reportable to the OIE (now WOAH), we are only rarely aware of their presence, or of the potential threat they may pose.
H6N6Today we've another study, published in Emerging Microbes & Infections, which characterizes the evolution and biological characteristics of H6 viruses in China, and finds additional evidence of increased adaptation to mammalian hosts.
This is a lengthy, and detailed, research article, which deserves to be read in its entirety. I've only posted the abstract and a few excerpts from the discussion. Follow the link to read:
Epidemiology, evolution, and biological characteristics of H6 avian influenza viruses in China
Xiaohao Xu, Qi Chen, Min Tan, Jia Liu, Xiyan Li, Lei Yang, show all
Accepted author version posted online: 28 Nov 2022
https://doi.org/10.1080/22221751.2022.2151380
Abstract
H6 avian influenza virus (AIV) is one of the most prevalent AIV subtypes in birds globally. To investigate the current situation and characteristics of H6 AIVs circulating in China, we analysed the epidemiology, genetic evolution and pathogenic features of this subtype. During 2000-2021, H6 subtype AIVs spread widely through Southern China and presented high host diversity.On analysing 171 H6 viruses isolated during 2009-2021, dynamic reassortments were observed among H6 and other co-circulating AIV subtypes, and these generated a total of 16 different genotypes. A few H6N6 strains possessed L226 and S228 mutations of hemagglutinin (H3 numbering), which may enhance the affinity of H6 viruses to human receptors.H6N6 viruses also exhibited divergent pathogenicity and growth profiles in vivo and in vitro. Some of the H6N6 viruses could infect mice without mammalian adaptation, and even caused death in this species. Therefore, our study H6 AIVs posed a potential threat to human healthdemonstrated that the H6 AIVs posed a potential threat to human health and highlighted the urgent need for continued surveillance and evaluation of the H6 influenza viruses circulating in the field.
(SNIP)
Discussion
In our study, the genotypic diversity of H6 viruses and 16 genotypes was revealed in the genome analysis, providing an indication of the intricate reassortment that occurs among these viruses during their active circulation with other viruses. The same characteristics were seen for the highly pathogenic avian influenza (HPAI) H5N1 virus and the H7N9 virus. For instance, during the 1997 outbreak in Hong Kong, H5N1 influenza viruses identified in this region were considered to be complicated reassortants that acquired the ability to infect and kill mammals gradually[23]. Previously, reassortment has contributed to the emergence and spread of pandemic influenza viruses in human populations[28]. However, an H3N8 AIV jumped the species barrier recently and caused acute respiratory distress syndrome in a child. Consequently, it was extremely likely to be a novel reassortant bearing certain genes from other influenza viruses[29]. Even though human-derived gene cassettes have not yet been reported in H6 AIVs, clearly, the possibility that such reassortments will occur someday exists.
H6 AIVs had been found to replicate in mice without preadaptation, but with less weight loss and an absence of death[30]. In this study, several of the H6N6 viruses caused severe clinical symptoms in mammals or eventual death. It has been demonstrated that a deletion in the NA stalk region increased the virulence of waterfowl-derived influenza viruses in poultry[26]. Interestingly, the two H6N6 isolates (JX24/09 and HN01/09), despite having totally different pathogenicities in mice (Figure 5A-B), shared the same nine amino acids deficit in this region and even possessed completely identical NA sequences. Hence, the real determinant of virulence and the molecular mechanism underlying the difference in the biological characteristics of H6 viruses deserve thorough explorations.
Moreover, molecular analysis suggested that the Q226L and G228S mutations existed in the HA proteins of our isolates and may have contributed to their increased affinity for the human-type receptor. Taken together, our findings suggest that H6 viruses pose an increasingly serious threat to public health.(Continue . . . )
In summary, given that H6 viruses have acquired the ability to replicate in mammalian hosts, we cannot rule out the possibility that they will eventually evolve into viruses with efficient transmissibility in mammals and even human populations via the accumulation of reassortments or mutations. Therefore, long-term surveillance of H6 AIVs in China is urgently needed.
The conventional wisdom is that H6 viruses are unlikely to pose a serious zoonotic threat, but a decade ago LPAI H7 viruses were also thought to be a weak cousin of HPAI H5N1, and incapable of producing the same level of virulence or spread in humans.
The emergence of LPAI H7N9 in China in 2013 - sporting a mortality rate (among those hospitalized) of 30% - has dispelled that notion. A severe human infection with LPAI H7N4 in China in 2018 showed this was not a fluke.
Admittedly, H6 sits pretty low on our novel flu worry list, but the more we know about these non-notifiable LPAI viruses, the less likely we are to be blindsided by a pandemic threat coming at us from out of left field.
