Functional Analysis of Influenza Virus PA-X and NS1 in Host Shutoff

Virus infection induces a wide range of host defense responses, such as the innate immune response and inflammation. Influenza A virus expresses two accessory proteins, NS1 and PA-X to induce general shutoff, which is one of the major viral strategies to counteract host antiviral activity and immune responses. Interestingly, the shutoff activity of PA-X and NS1 varies between the viruses. PA-X shutoff activity of avian viruses is much stronger than PA-X expressed by conventional human viruses. NS1 shutoff activity also varies between the viruses. We rescued and characterized 2009 pandemic H1N1 mutant virus that expresses reduced amount of PA-X. We showed that compared to the mutant virus, wild-type (wt) virus suppressed type I interferon response more efficiently and replicated rapidly in human respiratory cells than the mutant virus. Mice infected with the mutant virus had significantly lower levels of viral growth and greater expression of IFN-beta mRNA in their lungs than mice infected with the wt virus. Importantly, more anti-hemagglutinin and neutralizing antibodies were produced in the mice infected with the mutant virus, despite the lower level of virus replication in the lungs. Our data indicate that PA-X of the pandemic H1N1 virus has a strong impact on viral growth and the host innate and acquired immune responses to influenza virus. Furthermore, by characterizing deletion mutants, we found that PA-X-unique domain at the C-terminal region plays a major role in specific degradation of host mRNAs. Currently, we are analyzing the precise mechanism of how PA-X specifically targets and degrades host mRNAs, as well as functional interplay between PA-X and NS1 and its role on host adaptation.

Chaimayo C, Dunagan M, Hayashi T, Santoso N, Takimoto T. Specificity and functional interplay between influenza virus PA-X and NS1 shutoff activity. Plos Pathogen 14(11): e1007465. 2018. PMCID: PMC6289448

Dunagan M, Hardy K and Takimoto T. Impact of influenza A virus shutoff proteins on host immune responses. Vaccines 9:629. 2021. PMCID: PMC8230195

Desmet EA, Bussey KA, Stone R, Takimoto T. Identification of the N-terminal domain of influenza PA responsible for the suppression of host protein synthesis. J Virol 87:3108-18, 2013. PMCID: PMC3592176.

Hayashi T, MacDonald LA, Takimoto T. Influenza A virus protein PA-X contributes to viral growth and suppression of the host antiviral and immune responses. J Virol 89:6442-52, 2015. PMCID: PMC4474289.

Hayashi T, Chaimayo C, Takimoto T. Impact of influenza PA-X on host response. Oncotarget 6(23):19364-5, 2015. PMCID: PMC4637290.

Hayashi T, Chaimayo C, McGuinness J, Takimoto T. Critical role of the PA-X C-terminal domain of Influenza A virus in its subcellular localization and shutoff activity. J Virol 90:7131-41, 2016. PMCID: PMC4984632.

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