Abstract
Bats harbor many viruses, which are periodically transmitted to humans resulting in outbreaks of disease (e.g., Ebola, SARS-CoV). Recently, influenza virus-like sequences were identified in bats; however, the viruses could not be cultured. This discovery aroused great interest in understanding the evolutionary history and pandemic potential of bat-influenza. Using synthetic genomics, we were unable to rescue the wild type bat virus, but could rescue a modified bat-influenza virus that had the HA and NA coding regions replaced with those of A/PR/8/1934 (H1N1). This modified bat-influenza virus replicated efficiently in vitro and in mice, resulting in severe disease. Additional studies using a bat-influenza virus that had the HA and NA of A/swine/Texas/4199-2/1998 (H3N2) showed that the PR8 HA and NA contributed to the pathogenicity in mice. Unlike other influenza viruses, engineering truncations hypothesized to reduce interferon antagonism into the NS1 protein didn't attenuate bat-influenza. In contrast, substitution of a putative virulence mutation from the bat-influenza PB2 significantly attenuated the virus in mice and introduction of a putative virulence mutation increased its pathogenicity. Mini-genome replication studies and virus reassortment experiments demonstrated that bat-influenza has very limited genetic and protein compatibility with Type A or Type B influenza viruses, yet it readily reassorts with another divergent bat-influenza virus, suggesting that the bat-influenza lineage may represent a new Genus/Species within the Orthomyxoviridae family. Collectively, our data indicate that the bat-influenza viruses recently identified are authentic viruses that pose little, if any, pandemic threat to humans; however, they provide new insights into the evolution and basic biology of influenza viruses.
Highlights
Bats are present throughout most of the world and account for more than a fifth of mammalian species
Pandemic viruses are often reassortant viruses composed of vRNAs that are derived from multiple influenza A virus (IAV) lineages that previously circulated in swine and/or avian reservoirs (e.g., 1957 avian-human reassortant, 1968 avian-human reassortant, and 2009 avian-swinehuman reassortant)
We used synthetic genomics strategies to create wild type batinfluenza, or bat-influenza modified by substituting the surface glycoproteins with those of model influenza A viruses
Summary
Bats are present throughout most of the world and account for more than a fifth of mammalian species. They are natural reservoirs of some of the most deadly zoonotic viruses, including rabies virus, Ebola virus, Henipaviruses, and SARS coronavirus [1,2]. Pandemic viruses are often reassortant viruses composed of vRNAs that are derived from multiple IAV lineages that previously circulated in swine and/or avian reservoirs (e.g., 1957 avian-human reassortant, 1968 avian-human reassortant, and 2009 avian-swinehuman reassortant). The discovery of putative bat-influenza viruses expands the known host species reservoirs that may serve as a source of novel viruses, which is a major concern for public and animal health [4,5]
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