Host cells have coexisted with viruses from ancient times, thereby both of host and virus have affected each other's evolution. Influenza A virus (IAV) undergoes remarkably rapid evolution to evade host defense systems, whereas host has developed various antiviral responses such as antibodies and RNA silencing systems. Recently, two research groups nave reportea that human microRNAs (miR-323, miR-491 and miR-654) bind to influenza A virus polymerase ß subunit (PB1) mRNA and miR-let-7c also binds to M1 mRNA, inhibiting the replication of IAV respectively. These observations suggested that host microRNAs (miRNAs) have a potential as an antiviral system against IAV, however, it remained unclear whether or not IAV has conserved miRNA-target sites during their dynamic evolution. Here, we investigated evolutionary relationships between host miRNAs and IAV by using IAV sequence data for about a hundred years. Firstly, large-scale evolutionary networks detected both of dynamic mutations by interspecies-transmission processes and gradual mutations after transmitting to new hosts. Secondly, conservation analysis based on Shannon's information theory proved that miRNA-target sites in PB1 and Ml1 mRNAs were significantly conserved in human, swine and avian IAVs. Meanwhile, miR-323 and miR-491 were conserved in human and swine genome, and miR-let-7c was conserved in human, swine, and avian genome. Our results suggest that regulatory relationships of host miRNAs have been evolutionarily conserved in a broad host range, even though IAV mutate rapidly. We proposed following hypotheses : (1)host miRNAs targeted immutable regions of IAV mRNA, or (2) IAV might subvert host defense system to evade from host immune systems.
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