title: PB2-588I enhances 2009 H1N1 pandemic influenza virus virulence by increasing viral replication and exacerbating PB2 inhibition of beta interferon expression.
abstract: The 2009 pandemic H1N1 influenza virus (pdm/09) is typically mildly virulent in mice. In a previous study, we identified four novel swine isolates of pdm/09 viruses that exhibited high lethality in mice. Comparing the consensus sequences of the PB2 subunit of human isolates of pdm/09 viruses with those of the four swine isolate viruses revealed one consensus mutation: T588I. In this study, we determined that 588T is an amino acid mutation conserved in pdm/09 viruses that was exceedingly rare in previous human influenza isolates. To investigate whether the PB2 with the T5581 mutation (PB2-T558I) has an effect on the increased pathogenicity, we rescued a variant containing PB2-588I (Mex_PB2-588I) in the pdm/09 virus, A/Mexico/4486/2009(H1N1), referred to as Mex_WT (where WT is wild type), and characterized the variant in vitro and in vivo. The results indicated that the mutation significantly enhanced polymerase activity in mammalian cells, and the variant exhibited increased growth properties and induced significant weight loss in a mouse model compared to the wild type. We determined that the mutation exacerbated PB2 inhibition of mitochondrial antiviral signaling protein (MAVS)-mediated beta interferon (IFN-β) expression, and PB2-588I was observed to bind to MAVS more efficiently than PB2-588T. The variant induced lower levels of host IFN-β expression than the WT strain during infection. These findings indicate that the pdm/09 influenza virus has increased pathogenicity upon the acquisition of the PB2-T588I mutation and highlight the need for the continued surveillance of the genetic variation of molecular markers in influenza viruses because of their potential effects on pathogenicity and threats to human health.
authors: State Key Laboratory of Agriculture Microbiology, Huazhong Agriculture University, Wuhan, People's Republic of China.
authors: Zongzheng
authors: Z
authors: Zhao
authors: Chenyang
authors: C
authors: Yi
authors: Lianzhong
authors: L
authors: Zhao
authors: Shengyu
authors: S
authors: Wang
authors: Lishan
authors: L
authors: Zhou
authors: Yong
authors: Y
authors: Hu
authors: Wei
authors: W
authors: Zou
authors: Huanchun
authors: H
authors: Chen
authors: Meilin
authors: M
authors: Jin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004285:Dogs; D006801:Humans; D047468:Immunoprecipitation; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000472:pathogenicity*; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000235:genetics*; D008156:Luciferases; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics* / Q000378:metabolism*; D013045:Species Specificity; D013552:Swine; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism*; D014774:Virulence; D014779:Virus Replication / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016899:Interferon-beta; D008156:Luciferases; D012324:RNA-Dependent RNA Polymerase; D014764:Viral Proteins; C512612:MAVS protein, mouse; C057027:PB2 protein, Influenzavirus A