Inducible Guanylate-Binding Protein 7 Facilitates Influenza A Virus Replication By Suppressing Innate Immunity

Seasonal influenza is an acute respiratory infectious disease which seriously endangers human health and public health.It is caused by influenza virus.In recent years,due to the constant mutation of influenza virus,the transmission speed of influenza is faster,the morbidity and mortality are higher,and the mutated strains resistant to drugs used in clinical practice are also reported gradually,so it is an urgent task for researchers to find new drug targets and treatment schemes.Innate immunity is the first line of defense against virus invasion.Host proteins involved in the regulation of antiviral innate immunity have been continuously studied and reported.As host proteins have broad spectrum antiviral activity and are not easy to mutate,they can be used as targets to screen anti-influenza drugs.Guanylate-Binding Protein(GBP)family,with molecular weight between 67-69kDa and high homology in structure,all shares an N-terminal GTPase which can bind to GTP and hydrolyze it into GDP or GMP.GBPs were reported IFN-induced hydrolases which play roles in protecting the host cell's interior against a diverse group of invading pathogens.To date,seven human members(GBP1-GBP7)were identified,and GBP7 was reported to enhance cellular immunity in macrophages infected by listerial or mycobacterial to protect host.However,little is known about the relationship between GBP7 and influenza A virus(IAV)replication,and few reports have mentioned the role of GBP7 in the antiviral innate immune response.In this study,we show that GBP7 expression is significantly up-regulated in response to IAV infection in a mouse model,PBMCs,and A549 human lung epithelial cells.Performing the CRISPR-Cas9 system and overexpression approaches,for the first time,we show that GBP7 facilitates IAV replication by negatively modulating virus-triggered innate immune response.GBP7 knockout inhibits IAV replication by enhancing the expression of virus-induced type ? IFN(IFN-?,IFN-?),type ? IFN(IFN-?),proinflammatory cytokines(IL-6,IL-1?,TNF-?),and chemokines(IL-8,IP-10,CCL2,CCL5).By contrast,overexpression of GBP7 facilitates IAV replication by suppressing the expression of virus-induced type ? IFN,type ? IFN,proinflammatory cytokines,and chemokines.Furthermore,GBP7 knockout enhances nuclear factor-?B(NF-?B)activation and the phosphorylation of stat1,stat2.Our data indicate that GBP7 suppresses innate immune response to viral infection by inhibiting NF-?B and JAK-STAT signaling pathways.Taken together,upon IAV infection,the inducible GBP7 facilitates IAV replication by suppressing innate immune response to viral infection.We show that arbidol induces GBP7 expression,and arbidol suppresses IAV-induced NF-?B pathway and proinflammatory cytokines.Our findings highlight the negative role of GBP7 in virus-triggered innate immunity,suggesting that GBP7 could be a potential therapeutic target for controlling IAV infection.