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.
  1. Arturo Barbachano-Guerrero
  2. Daniel R Perez  Is a corresponding author
  3. Sara L Sawyer  Is a corresponding author
  1. University of Colorado Boulder, United States
  2. 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).

How avian influenza viruses adapt to mammals.

(A) One way that avian viruses can adapt to mammals is through virus reassortment, as shown here. The avian virus (red) reassorts with another influenza virus that is already adapted to mammals (green), yielding a new mammalian-adapted virus. For this to happen, a single individual must be infected by both viruses simultaneously. (B) The other way that avian viruses can adapt to mammals is by direct infection and subsequent adaptation, as is illustrated here. As an avian virus (red) starts to spread between individuals in a mammalian population, it can acquire mutations that make it better at infecting mammals (an evolutionary intermediate is shown in blue). Eventually it may become well-adapted to infecting mammals (green). (C) Chen at al. isolated H3N2 canine influenza viruses from samples collected between 2012 and 2019 (middle columns), and tested them for a range of phenotypic properties that are associated with influenza viruses being able to infect mammals (rows). As controls, they included avian H3N2 (left column) and human H3N2 (right column) viruses. They found that, over time, the canine H3N2 virus gained multiple properties that make it compatible with mammals (green squares), with several of the key adaptations occurring around or after 2016/2017. Yellow squares indicate intermediate phenotypes. A blank square indicates that the test was not performed.

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.


Article and author information

Author details

  1. Arturo Barbachano-Guerrero

    Arturo Barbachano-Guerrero is in the BioFrontiers Institute, University of Colorado Boulder, Boulder, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7483-839X
  2. Daniel R Perez

    Daniel R Perez is in the Poultry Diagnostic and Research Center, Department of Population Health, College of Veterinary Medicine, University of Georgia, Athens, United States

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6569-5689
  3. Sara L Sawyer

    Sara L Sawyer is a Senior Editor at eLife, and is in the BioFrontiers Institute and the Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6965-1085

Publication history

  1. Version of Record published: April 11, 2023 (version 1)


© 2023, Barbachano-Guerrero et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 1,813
    Page views
  • 192
  • 1

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Arturo Barbachano-Guerrero
  2. Daniel R Perez
  3. Sara L Sawyer
Viruses: How avian influenza viruses spill over to mammals
eLife 12:e86051.

Further reading

    1. Epidemiology and Global Health
    2. Medicine
    Jeffrey Thompson, Yidi Wang ... Ulrich H von Andrian
    Research Article Updated


    Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19.


    A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak.


    A total of 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. A total of 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR = 0.22; 95%CI:0.21–0.23; p<0.001), COVID-19 diagnosis (OR = 0.23; 95%CI:0.22–0.24; p<0.001), and COVID-19-related hospitalization (OR = 0.26; 95%CI:0.24–0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR = 0.23; 95%CI:0.22–0.23; p<0.001) or pneumonia (OR = 0.32; 95%CI:0.31–0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2.


    Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes.


    This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to UHvA) and a CRI Irvington postdoctoral fellowship, CRI2453 (to PH).

    1. Epidemiology and Global Health
    Tianyi Huang

    A large observational study has found that irregular sleep-wake patterns are associated with a higher risk of overall mortality, and also mortality from cancers and cardiovascular disease.