Friday, April 14, 2023

Increased Public Health Threat of Avian-origin H3N2 Influenza Virus During Evolution in Dogs (Revisited)



#17,406

Last October we looked at a lengthy (57-page) preprint called Increased Public Health Threat of Avian-origin H3N2 Influenza Virus During Evolution in Dogs from researchers in China who warned on the continued evolution of canine H3N2, which appears to be moving towards becoming a more `humanized' virus.

Canine H3N2 first appeared in South Korea in 2007, and analysis showed that the HA and NA genes of the A/canine/Korea/01/2007 (H3N2) isolate were closely related to those identified in 2003 from chickens and doves in South Korea.

Canine H3N2 arrived to the United States in 2015 (see CDC Statement On H3N2 Canine Influenza In Chicago Region) and has since spread nationally. In 2017, the CDC added Canine H3N2 to their IRAT (Influenza Risk Assessment Tool) list of novel flu viruses with zoonotic potential.

H3N2: [A/canine/Illinois/12191/2015]

The H3N2 canine influenza virus is an avian flu virus that adapted to infect dogs. This virus is different from human seasonal H3N2 viruses. Canine influenza A H3N2 virus was first detected in dogs in South Korea in 2007 and has since been reported in China and Thailand. It was first detected in dogs in the United States in April 2015. H3N2 canine influenza has reportedly infected some cats as well as dogs. There have been no reports of human cases.

Summary:  The average summary risk score for the virus to achieve sustained human-to-human transmission was low risk (less than 4). The average summary risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was in the low risk range (less than 4).

Over the past decade we've looked at several studies on the evolution of this avian-origin canine H3N2 virus, including:

Dogs and cats have increasingly been cited as potential hosts and `mixing vessels' for novel flu viruses. You can find a few (of many) past blogs here, here, and here).

The above mentioned preprint was published this past week by eLife (see below). While this is an often technical, and highly detailed paper, the authors manage to convey the gist in the abstract below.
Abstract

Influenza A viruses in animal reservoirs repeatedly cross species barriers to infect humans. Dogs are the closest companion animals to humans, but the role of dogs in the ecology of influenza viruses is unclear. H3N2 avian influenza viruses transmitted to dogs around 2006 and have formed stable lineages. The long-term epidemic of avian-origin H3N2 virus in canines offers the best models to investigate the effect of dogs on the evolution of influenza viruses.

Here, we carried out a systematic and comparative identification of the biological characteristics of H3N2 canine influenza viruses (CIVs) isolated worldwide over 10 years. We found that, during adaptation in dogs, H3N2 CIVs became able to recognize the human-like SAα2,6-Gal receptor, showed gradually increased hemagglutination (HA) acid stability and replication ability in human airway epithelial cells, and acquired a 100% transmission rate via respiratory droplets in a ferret model. We also found that human populations lack immunity to H3N2 CIVs, and even preexisting immunity derived from the present human seasonal influenza viruses cannot provide protection against H3N2 CIVs.

Our results showed that canines may serve as intermediates for the adaptation of avian influenza viruses to humans. Continuous surveillance coordinated with risk assessment for CIVs is necessary.
 
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While we've seen an earlier version of this before, eLife has also published an `Insight' background feature on this report.  Follow the link for the full report, including references.
Viruses: How avian influenza viruses spill over to mammals
The H3N2 canine influenza virus – which originally came from birds – is evolving to become more transmissible between dogs. 
Apr 11, 2023 https://doi.org/10.7554/eLife.86051 Open access

Arturo Barbachano-Guerrero, Daniel R Perez ,Sara L Sawyer
University of Colorado Boulder, United States; University of Georgia, United States

Picture your local lake covered with migrating geese, ducks or other waterfowl. Even though you don’t hear any coughing, you might well be witnessing ‘flu season’ for birds. Influenza viruses cause gastrointestinal infections in birds, and are spread when birds defecate in water that other birds then drink (Caliendo et al., 2020). Sometimes, however, avian influenza viruses make their way into mammals, including humans, and cause respiratory infections: how does this happen?

Waterfowl are the main natural reservoir for influenza viruses, and influenza viruses that infect humans and other mammals originally came from birds. This spillover can happen in two ways. The first way involves special mammalian hosts (like pigs) that can be infected by both avian and mammalian influenza viruses (Figure 1A). Occasionally, an individual from one of these species becomes simultaneously infected with both types of virus, and the two viruses exchange gene segments to form a novel virus that retains the ability to infect mammals. This process – which is known as gene reassortment – is what happened to start human influenza pandemics in 1957 and 1968 (Harrington et al., 2021).

Figure 1
How avian influenza viruses adapt to mammals.    (more)
The second way that spillover can happen involves a mammal getting directly infected with a bird virus (Figure 1B). This individual then transmits this bird virus to others in its same species. If infection of the new species is sustained over time and within many individuals, the avian virus will experience natural selection for genetic mutations that make it more and more compatible with the mammalian species (Lipsitch et al., 2016).

Now, in eLife, Yipeng Sun (Chinese Agricultural University) and co-workers – including Mingyue Chen and Yanli Lyu as joint first authors – report the results of experiments which shed light on how a virus that normally infects birds is spreading and evolving in dogs around the world via this second form of spillover (Chen et al., 2023). It is important to understand how this happens, because there are avian viruses currently adapting to several different mammalian species via this direct bird-to-mammal pathway (Meng et al., 2022). Each of these ongoing evolution experiments could, at least in theory, yield a human-adapted virus.

There are only a small number of influenza viruses that humans live with, and these constitute our seasonal influenza virus repertoire. The same is true for dogs, and there are just two influenza viruses that dogs transmit consistently between each other – H3N2 and H3N8. The H3N2 canine influenza virus was first found in 2006 in Guangdong Province in China, and research revealed that its genome was closely related to that of the H3N2 influenza viruses found in birds (Li et al., 2010). The virus has since spread out of Asia and was first identified in dogs in the United States in 2015.

To study the evolution of H3N2 in dogs, Chen et al. collected 4174 tracheal swab samples from sick dogs in veterinary hospitals and kennels. The oldest sample dated back to 2012 and the most recent was from 2019. In addition to sequencing the viruses in these samples and analyzing them phylogenetically, the researchers also tested the viruses from a subset of the samples for a range of phenotypic properties that are associated with bird influenza viruses being able to infect mammals (Lipsitch et al., 2016). They found that the H3N2 canine influenza viruses have gained a number of these phenotypic properties since 2012, making them more and more adapted to mammals as time goes by (Figure 1C). To draw these conclusions, Chen et al. performed infections in dogs and ferrets, and also examined the ability of these viruses to infect human cells in tissue culture.

The researchers were also able to map some of the adaptions to specific sets of genetic changes in the virus genome. Some of these adaptations of avian H3N2 to dogs had been observed before, but prior studies focused on strains from 2017 or earlier (Martinez-Sobrido et al., 2020; Tangwangvivat et al., 2022). The remarkable experimental virology demonstrated in these studies is laborious, but critical for assessing the danger that animal viruses pose to humans (Warren and Sawyer, 2023).

Just because the H3N2 canine influenza virus is perfecting itself for dogs does not mean that it will infect humans. Once an avian influenza virus has perfected itself for a particular mammalian species, such as dogs, we don’t know the details of what then dictates its transmission to a different mammalian species, such as humans (Warren and Sawyer, 2019). Thankfully, there have been no reports to date of humans being infected with canine influenza virus.

         (Continue . . . ) 


While a direct jump of an avian virus from a bird to a human may seem the most obvious threat, a jump to an intermediate host - like a dog, a pig, or a cat - could provide an avian virus with additional opportunities to acquire the necessary mammalian adaptations it would need to spark a pandemic. 

In 2016, we saw an avian H7N2 virus spread rapidly across hundreds of cats in several New York City animals shelters. It was likely introduced to the captive feline population by a stray which had killed and eaten an infected bird just prior to being housed in the facility.  

 Cats Infected With H7N2 - NYC 2016
Regardless, it spread like wildfire, and in the process infected at least 2 veterinary workers (see J Infect Dis: Serological Evidence Of H7N2 Infection Among Animal Shelter Workers, NYC 2016), despite the use of PPEs (see photo above). 

While apparently well-adapted to cats, avian H7N2 wasn't ready for prime time in humans, and a bigger crisis was averted. 

But this incident reminds us that companion animals can serve a a bridge for novel viruses to jump to humans, which makes canine H3N2 a virus well worth our attention. 

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