#16,725
Because human adapted novel flu viruses tend to emerge and spark global pandemics with some regularity (2009, 1968, 1957, 1918 . . .) we keep a sharp eye out whenever we see signs that a new threat is emerging.
And since all of the known influenza pandemics going back 120+ years have been sparked by either an H1, H2, or H3 virus, we pay particular attention to these HA subtypes.
We don't discount the possibility that an H5, H7, H9 (or some other) subtype could spark a pandemic, but recent history suggests that H1, H2, and H3 viruses may have an easier time adapting to humans (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?).
In 1968, when the world was dominated by the H2N2 flu virus - an avian H3 emerged (H3N2) in Hong Kong - and sparked a pandemic that quickly supplanted H2N2 and killed more than 1 million people.
This virus was a reassortment consisting of 2 genes from a low path avian influenza H3 virus, and 6 genes from H2N2. And while it was not initially as deadly as the 1957 or 1918 pandemics - it is still with us 54 years later - and has caused millions of additional deaths over the past half century.
Last week we saw the first known modern human infection with an avian H3N8 virus (see China: NHC Confirms Human Avian H3N8 Infection In Henan Province), and while this could turn out to be a one-off (or rare) occurrence, it is a reminder that the next novel flu pandemic could emerge at any time.
We've been watching the evolution and spread of avian (AIV), canine (CIV), and equine (EIV) H3Nx influenza viruses with considerable interest for the past two decades. In 2004 H3N8 EIV mutated and jumped to dogs creating a CIV, while in 2007 an avian H3N2 virus in South Korean ducks jumped to dogs creating an H3N2 CIV.
We've also seen cats infected with canine H3N2, pigs experimentally infected with H3N2 AIV, and large die-offs of seals from an avian H3N8 virus.
Six months ago, in CCDC Weekly: Epidemiological and Genetic Characteristics of the H3 Subtype Avian Influenza Viruses in China, we looked at a rare, detailed, and highly informative overview of avian H3 viruses detected in wild birds and poultry across China. One which highlighted both H3N2 and H3N8 as growing threats.
Prior to that, in 2019's Emerg. Microbes & Inf: Avian H3N2 Viruses Bind To Human-Type Receptors & Transmit In Guinea Pigs & Ferrets, we saw evidence of mammalian adaptation of some avian H3N2 viruses in China.
And repeatedly over the past decade we've seen evidence that canine H3N2 continues to reassort, and adapt to other species.
A Canine H3N2 Virus With PA Gene From Avian H9N2 - Korea
Canine H3N2 Reassortant With pH1N1 Matrix Gene
Interspecies Transmission Of Canine H3N2 In The Laboratory
Of the 22 novel flu viruses currently listed by the CDC IRAT tool as having some pandemic potential, three of them are H3Nx (2 swine, 1 canine).
This is a long and detailed report. I've only excerpted the Abstract and Discussion sections, so you'll want to follow the link to read it in its entirety. I'll have a brief postscript when you return.
Qiucheng Yao1†, Wenhong Mai1†, Yuexiao Lian2†, Mengdi Zhang1, Qiang Yao3, Caiyun Huang4, Ye Ge1* and Zhihui Zhao1*
Avian-to-mammal transmission and mammalian adaptation of avian influenza virus (AIV) are threats to public health and of great concern. The H3 subtype of influenza virus has low pathogenicity and is widely distributed in humans, canines, equines and avians.In 2018–2019, we isolated six H3N2 subtype influenza viruses from 329 samples acquired from ducks on the Leizhou Peninsula, China, as part of an ongoing virus surveillance program. All viruses were analyzed by whole-genome sequencing with subsequent genetic comparison and phylogenetic analysis. Phylogenetic analysis demonstrated that reassortment of these viruses has occurred among different hosts and subtypes.Some of the H3 AIV isolates have similar genes as subtypes H5 and H7 of highly pathogenic avian influenza viruses (HPAIVs). Most importantly, one strain of H3N2 virus is a novel reassortant influenza virus containing HA and PB2 segments from canine H3N2 virus. The time of most recent common ancestor (tMRCA) data indicated that this reassortant H3N2 virus might have emerged in 2011–2018.The findings suggest that the viruses studied here have undergone multiple reassortment events. Our results provide a framework for understanding the molecular basis of host-range shifts of influenza viruses and we should pay more attention to canine which lived with avian together.
(SNIP)
Discussion
The natural reservoir of influenza A virus is waterfowl. Normally, waterfowl viruses are not adapted to infect and spread in the human population. Sometimes, through reassortment or whole host-shift events, genetic material from waterfowl viruses is introduced into the human population and causes a worldwide pandemic. AIV poses a threat to both humans and animals. Humans were infected by the H5N1 and H9N2 subtypes of AIV in Southeast Asia in 1997 and the H5N6 subtype of AIV in China, revealing that AIVs can traverse the species barrier from birds to humans (Zou et al., 2020).
The H3N2 virus in chickens from live poultry markets (LPMs) was first detected in Central China in 2001 (Liu et al., 2003). Since 2009, H3N2 AIVs have been regularly reported in China (Zhou et al., 2011). As of September 12, 2021, there were 104255 H3N2 influenza virus strains in the GISAID database, of which only 5,546, including 154 avian-originated strains, were isolated from animals. H3N2 AIVs are LPAIVs, and infectious poultry generally have mild symptoms and lack control and prevention. However, H3N2 AIVs can donate their gene segments to HPAIVs and thereby cause accelerated recombination or mutation, potentially causing the next pandemic and threatening public health.
Here, we extensively characterized 6 avian H3N2 viruses that were isolated from duck farms on the Leizhou Peninsula, China, and found that the H3N2 viruses circulating in avian species in nature have undergone frequent reassortment and formed complicated genotypes. Viral reassortment is the source of emergence of deadly HPAI viruses that are transmissible to mammals and are prone to adaptive evolution in their new hosts (Guo et al., 2019). It is still disputed whether the infamous 1918 Spanish flu pandemic was caused by a reassortant strain evolved in mammals or an entirely avian-like virus that adapted to humans (Taubenberger et al., 2005).
Exchange of gene segments through reassortment is a major feature of influenza A virus evolution and frequently contributes to the emergence of novel epidemic, pandemic, and zoonotic strains. In particular, some gene segments, such as the HA segment of PY8/H3N2, include surface genes from canines. Therefore, it has been reported that H3N2 CIV originated from avians. Our analyses suggested that the genes can circulate among different hosts and be transmitted from avians to mammals and vice versa. In addition, the tMRCA data indicated that the reassortment leading to the emergence of this H3N2 virus might have occurred in 2017. Importantly, the PB1, PA, NP and M genes of the novel PY8/H3N2 isolate show the highest nucleotide similarities to those of the avian H5N6 strains. The PB2 gene originated from canine virus isolated in Beijing, and the NA and NS genes originated from avian in Jiangsu and Guangxi. These findings suggest that reassortment occurred in wild birds and/or domestic poultry (Figure 4).
The findings suggest a threat of these viruses with respect to influenza virus-acquired ability of transmission across species. During routine monitoring, we found that duck farms were located in remote locations far from residential areas, with little chance of outside contact. However, every duck farm had one or more dogs as guard dogs. We speculate that the viruses with canine-originated gene segments emerged because of long-term close contact between ducks and guard dogs. Additionally, whether dogs, as the closest companions of humans, could facilitate the transmission of CIV to humans needs further investigation. However, we found evidence that canines may have donated canine-origin gene segments to avian influenza viruses that lead to gene reassortment.
Some of the H3 AIV isolates had gene segments (PB2 and N2 genes) similar to those of not only LPAIVs (H3 and H9 AIVs) but also H5 and H7 HPAIVs. This result is consistent with reports that genetic reassortment involving H3 AIV and H5N6 HPAIV appeared in poultry in China. The origin analysis of the six H3N2 viruses isolated in this study indicated that most of the gene segments originated from different subtypes of influenza viruses previously detected in chickens and ducks, suggesting that different influenza viruses circulate together and that gene reassortment occurs frequently among these avian species.
The analysis of the protein sequences of surface and inner genes of the six H3N2 AIVs in this study suggest that circulating AIVs may have the potential to bind the human-type receptor and that antiviral drugs and amantadine may be ineffective for treating poultry infected with these AIVs. All six viruses have the ability to adapt to mammalian hosts and enhance virulence, thus posing severe threats to both public health and poultry markets.
Conclusion
In conclusion, the analysis of the six strains of AIVs we isolated proved that their genomes have undergone reassortment with the H1N3, H3N8, H5N6, H6N2, H7N7, and H9N2 subtypes of AIV. Our study has thus revealed the risks to human health posed by H3N2 avian viruses and emphasizes the importance of continuous monitoring and evaluation of H3N2 influenza viruses circulating in poultry.
Although we spend a lot of time looking at HPAI H5 or H7 avian viruses that might spark a pandemic - mostly because of their much higher (30%-50%) fatality rates in humans - history suggests we are more likely to see an H1, H2, or H3 (avian/swine/canine) novel flu virus spark the next pandemic.
Unfortunately, our knowledge of what is going on in the wild is quite limited, and the next pandemic is likely to emerge with very little (if any) warning.
Better surveillance will help, but our only realistic recourse is to get prepared, and stay prepared, to deal with the next pandemic. Regardless of its origin.
