Abstract
The influenza A virus (IAV) can be recognized by retinoic acid-inducible gene I (RIG-I) to activate the type I interferon response and induce antiviral effects. The virus has evolved several strategies to evade the innate immune response, including non-structural protein 1 (NS1) and its polymerase subunits. The mechanism by which NS1 inhibits interferon-β (IFN-β) is well understood, whereas the mechanism by which polymerase acid protein (PA) inhibits IFN-β remains to be elucidated. In this study, we observed that the IAV PA protein could inhibit the production of IFN-β and interferon-stimulated genes induced by Sendai virus through interferon regulatory factor 3 (IRF3), but not through nuclear factor-kappaB (NF-kappaB). In addition, PA inhibited IFN-β induction by RIG-I, melanoma differentiation-associated gene 5, mitochondria antiviral signaling protein, TANK-binding kinase 1, inhibitor of nuclear factor kappa-B kinase-ε (IKKε), and IRF3 overexpression. Furthermore, PA interacted with IRF3 to block its activation. The N-terminal endonuclease activity of PA was responsible for its interaction with IRF3 and inhibition of the IFN-β signaling pathway. In summary, our data reveal the mechanism by which IAV PA inhibits the IFN-β signaling pathway, providing a new mechanism by which the virus antagonizes the antiviral signaling pathway.
Highlights
Type I interferon (IFN-I) is the first defense line of the host antiviral response and leads to broadspectrum antiviral effects [1,2,3,4]
Luciferase assays revealed that all subtypes of PA could strongly inhibit Sendai virus (SEV)- and Poly(I:C)-induced IFN-β promoter activity (Figure 1A), supporting the hypothesis that Influenza A virus (IAV) PA plays a role in inhibition of the IFN-β signaling pathway [21]
The influenza virus RNA polymerase is a heterotrimeric complex consisting of the PB2, PB1, and PA subunits, all of which are required for viral RNA (vRNA) transcription and replication [15,16,17]
Summary
Type I interferon (IFN-I) is the first defense line of the host antiviral response and leads to broadspectrum antiviral effects [1,2,3,4]. The activation of innate immunity leads to a cascade of downstream signaling pathways and results in the activation of IFN-I and a variety of inflammatory cytokines [5, 6] Both retinoic acid-inducible gene 1 (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5) [5, 7,8,9] can recognize IAV RNA and bind to the mitochondria antiviral signaling protein (MAVS, known as IPS-1), thereby activating TANK-binding kinase 1 (TBK-1) and inhibitor of nuclear factor kappa-B kinase (IKK).
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