tetano
Editor, Senior Moderator
J Virol. 2015 Apr 8. pii: JVI.00319-15. [Epub ahead of print]
[h=1]Influenza A virus protein PA-X contributes to viral growth and suppression of the host antiviral and immune responses.[/h] Hayashi T[SUP]1[/SUP], MacDonald LA[SUP]1[/SUP], Takimoto T[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza virus infection causes global inhibition of host protein synthesis in infected cells. This host shutoff is thought to allow viruses to escape from the host antiviral response, which restricts virus replication and spread. Although the mechanism of host shutoff is unclear, a novel viral protein expressed by ribosomal frameshifting PA-X, was found to play a major role in influenza virus-induced host shutoff. However, little is known about the impact of PA-X expression on currently circulating influenza A virus pathogenicity and the host antiviral response. In this study, we rescued a recombinant influenza A virus A/California/04/09 (H1N1, Cal) containing mutations at the frameshift motif in the PA gene (Cal PA-XFS). Cal PA-XFS expressed significantly less PA-X than Cal wild type (WT). Cal WT, but not Cal PA-XFS, induced degradation of host β-actin mRNA and suppressed host protein synthesis, supporting the idea that PA-X induces host shutoff via mRNA decay. Moreover, Cal WT inhibited IFN-β expression and replicated more rapidly than Cal PA-XFS in human respiratory cells. Mice infected with Cal PA-XFS had significantly lower levels of virus growth and enhanced expression of IFN-β mRNA in their lungs than mice infected with Cal WT. Importantly, more anti-hemagglutinin and neutralizing antibodies were produced in Cal PA-XFS-infected mice than Cal WT-infected mice, 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 response to influenza virus.
[h=4]IMPORTANCE:[/h] Virus-induced host protein shutoff is considered to be a major factor to allow viruses to evade innate and acquired immune recognition. We provide evidence that the 2009 H1N1 influenza A virus protein PA-X plays a role in virus replication and inhibition of host antiviral response by means of its host protein synthesis shutoff activity both in vitro and in vivo. We also demonstrated that while growth of Cal PA-XFS was attenuated in the lungs of infected animals, this mutant induced a stronger humoral response than Cal WT. Our findings clearly highlight the importance of PA-X in counteracting the host innate and acquired immune response to influenza virus, an important global pathogen. This work demonstrates that inhibition of PA-X expression in influenza virus vaccine strains may provide a novel way of safely attenuating viral growth while inducing a more robust immune response.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25855745 [PubMed - as supplied by publisher]
[h=1]Influenza A virus protein PA-X contributes to viral growth and suppression of the host antiviral and immune responses.[/h] Hayashi T[SUP]1[/SUP], MacDonald LA[SUP]1[/SUP], Takimoto T[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Influenza virus infection causes global inhibition of host protein synthesis in infected cells. This host shutoff is thought to allow viruses to escape from the host antiviral response, which restricts virus replication and spread. Although the mechanism of host shutoff is unclear, a novel viral protein expressed by ribosomal frameshifting PA-X, was found to play a major role in influenza virus-induced host shutoff. However, little is known about the impact of PA-X expression on currently circulating influenza A virus pathogenicity and the host antiviral response. In this study, we rescued a recombinant influenza A virus A/California/04/09 (H1N1, Cal) containing mutations at the frameshift motif in the PA gene (Cal PA-XFS). Cal PA-XFS expressed significantly less PA-X than Cal wild type (WT). Cal WT, but not Cal PA-XFS, induced degradation of host β-actin mRNA and suppressed host protein synthesis, supporting the idea that PA-X induces host shutoff via mRNA decay. Moreover, Cal WT inhibited IFN-β expression and replicated more rapidly than Cal PA-XFS in human respiratory cells. Mice infected with Cal PA-XFS had significantly lower levels of virus growth and enhanced expression of IFN-β mRNA in their lungs than mice infected with Cal WT. Importantly, more anti-hemagglutinin and neutralizing antibodies were produced in Cal PA-XFS-infected mice than Cal WT-infected mice, 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 response to influenza virus.
[h=4]IMPORTANCE:[/h] Virus-induced host protein shutoff is considered to be a major factor to allow viruses to evade innate and acquired immune recognition. We provide evidence that the 2009 H1N1 influenza A virus protein PA-X plays a role in virus replication and inhibition of host antiviral response by means of its host protein synthesis shutoff activity both in vitro and in vivo. We also demonstrated that while growth of Cal PA-XFS was attenuated in the lungs of infected animals, this mutant induced a stronger humoral response than Cal WT. Our findings clearly highlight the importance of PA-X in counteracting the host innate and acquired immune response to influenza virus, an important global pathogen. This work demonstrates that inhibition of PA-X expression in influenza virus vaccine strains may provide a novel way of safely attenuating viral growth while inducing a more robust immune response.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25855745 [PubMed - as supplied by publisher]