Inhibition Of IFN-? Production By Marek's Disease Virus VP23 Protein Through Modulation Of DNA Sensing Signaling Pathway

Marek's disease virus(MDV)is a highly pathogenic and oncogenic herpesvirus of chickens.Apart from being a widespread economically important disease of poultry worldwide,Marek's disease(MD)has contributed significantly to our understanding of herpesvirus-associated oncogenicity.Innate immune systems produce a series of cytokines to resist the virus invasion through the recognition of virus by pattern recognition receptors.During DNA virus infection,viral nucleic acids are recognized by DNA receptors,thereby initiating downstream signaling cascades and inducing IFN-I(type I interferons).The cGAS-STING signaling pathway is the most important DNA signaling pathway in human and mammalian cells.However,DNA receptor-mediated IFN-I signaling pathway has not been reported in avian viruses related studies.In this study,we found that IFN-? production was inhibited during the late phases of MDV infection,suggested that MDV-infection suppressed IFN-? signaling pathway during viral infection.To determine the function of the cGAS-STING DNa sensing pathway in the induction of IFN-? during MDV infection,we down-regulated the expression of cGAS and STING,and found that the transcription and expression of IFN-? was significantly inhibited.It was indicated that the cGAS-STING signaling pathway is critical for the production of MDV-induced IFN-P.Using the dual luciferase reporter system,we obtained 5 viral proteins that significantly inhibited the production of IFN-? mediated by cGAS-STING.In this study,we further incesteigated the machanisms of VP23-induced inhibition of the cGAS-STING pathway.We found that VP23-overexpression significantly inhibited IFN-P production induced by ISD transfection and HVT infection,while knockdown of VP23 enhanced IFN-P production during MDV infection and decreased viral replication,which confirmed the role played by VP23 in the inhibition of the DNA sensing pathway.Further,we found that VP23 inhibited the activation of transcription factor IRF7 without a significant effect on the activation of NF-?B.VP23 blocks the nuclear translocation of IRF7 by suppressing its phosphorylation and dimerization.The coimmunoprecipitation assay indicated that VP23 interacts with IRF7 and disrupts the TBK1-IRF7 association,thereby preventing IRF7 activation and inhibiting IFN-P production in VP23-expressing cells.In summary,we demonstrate that the cGAS-STING DNA sensing pathway plays important roles in IFN-? response upon MDV infection.Moreover,MDV protein VP23 is an efficient IFN-? inhibitor.VP23 interacts with chicken IRF7 and blocks the binding of TBK1 to IRF7,leading to the suppression of IRF7 activation and impaired IFN-? response.These findings expand our understanding of the pathogenesis of MDV and accelerate the development of more effective control strategies.