The Mechanisms Of Nuclear Receptor NR4A1 In Regulation Of Host Defense Against Influenza Virus Infection

Influenza A virus(IAV)is an important zoonotic pathogen with a wide host range with pig and poultry are two important hosts of IAV.IAV infection can cause severe respiratory diseases in human and animals,leading to a number of death in severe cases.Although vaccination can significantly reduce IAV infection and occurrence,the continuous mutation and recombination of the virus has brought severe challenges to the production and application of vaccines.Therefore,searching for new anti-influenza virus drug targets is of great significance to formulating the prevention,control and treatment of influenza virus infection.Recent studies have revealed that host factors are considered to be potential IAV therapeutic targets.It has been shown that Nr4a1 is regulated by a variety of virus,suggesting that Nr4a1 may be an important host factor involved in regulation of IAV infection.However,the regulation of IAV replication by Nr4a1 and how IAV regulates Nr4a1 expression remain unknowns.In order to clarify the role of Nr4a1 in IAV infection,we used mouse primary bone marrow macrophages(BMDMs)as a model and found that IAV infection can significantly inhibit the expression of Nr4a1.Further studies revealed that PA and PB2 of IAV were the two key proteins that inhibited the expression of Nr4a1.To investigate the role of Nr4a1 in IAV replication,we generate stable cell lines that expressing Nr4a1 or sh RNAs targeting Nr4a1 by using lentiviral system in i BMDMs.We showed that Nr4a1 expression could significantly inhibit replication of IAV while Nr4a1 konckdown significantly promoted replication of IAV,suggesting that Nr4a1 is an important host factor to regulate IAV replication.To understand the mechanisms by which Nr4a1 regulates IAV replication,we examined the effect of Nr4a1 on expression of Ifnb and interferon-stimulated genes(ISGs).The results showed that Nr4a1 expression significantly promoted Poly(I:C)and virus-induced expression of Ifnb;Nr4a1knockdown significantly inhibited expression of Ifnb and ISGs.Futher studies found that deficiency or knockdown of Nr4a1 inhibited the phosphorylation of the interferon regulatory factor IRF3,indicating that Nr4a1 is positive regulator of type I IFNs.In summary,we found that IAV infection can inhibit the production of type I IFN by downregulating the expression of Nr4a1,thereby promoting self-replication.Hence,our study demonstrated that downregulation of Nr4a1 might be a novevl mechanism for IAV to evade innate immunity,indicating that Nr4a1 may be a potential pharpeutical target for development of antiviral drug for IAV infection.