The Negative Role And Its Underlying Mechanisms Of TIPE2 In Regulating RNA Virus Infection

Objective:Acute respiratory tract infection(ARTI)is the most common type of infectious disease in children.Virus infection might account for as many as 90%of ATRI and the majority of virus was RNA virus.In addition to the influenza virus,there is no effective treatment for RNA virus infection.So we tried to explore the mechanism of regulating of RNA virus infection,which might be to find a new approach to treatment of RNA virus infection in the future.Tumor necrosis factor-a-induced protein 8-like 2(TIPE2),who is a member of the tumor necrosis factor-a-induced protein-8(TNFAIP8)family,could be a negative regulator of immune response and prevent hyperresponsiveness and sustain immune homeostasis.However,the regulatory role of TIPE2 in RNA virus infection and the effect of TIPE2 in the signaling pathway after RNA virus infection are poorly clarified.This study aims to investigate the effect and underlying mechanisms of TIPE2 on RNA virus infection.Methods:We acquired the peripheral blood mononuclear cells from 154 patients infected with Respiratory Syncytial Virus(RSV)(the most common virus in children)and 66 control healthy children,and detected the TIPE2 mRNA expression.We also detected the expression of TIPE2 in macrophages in vitro after vesicular stomatitis virus(VSV)(the common virus used in research)and RSV infection.Meanwhile,we tried to explore the effect and its underlying mechanisms of TIPE2 in regulating RNA virus response through gain and loss of function.Results:In our study,we detected a significantly decrease of TIPE2 mRNA in peripheral blood mononuclear cells(PBMCs)from 154 cases of children infected with RSV comparing to that in PBMCs from 66 control healthy children.We also found the expression of TIPE2 was decreaseed after VSV and RSV infection in vitro.It implied that TIPE2 might play a critical role in anti-RNA viral immunity.Further we observed that TIPE2-/-macrophages showed more susceptible to VSV infection and higher levels of VSV replication after VSV infection in vitro.And we also found that the deficiency of TIPE2 enhanced type-I IFNs and inflammatory cytokines production by macrophages,moreover,overexpression of TIPE2 dampened the capacity of macrophages to produce type-I IFNs and inflammatory cytokines.Moreover,TIPE2 could restrain the activation of TBK1 and IRF3 signaling pathway,thus inhibiting the production of type I interferon and inflammatory cytokines.Conclusions:Taken together,our results suggested that TIPE2 could suppress type-I interferon and inflammatory cytokines production induced by RNA virus through inhibiting the activation of TBK1,IRF3 signaling pathway.This research uncovered an important regulatory role of TIPE2 in innate antiviral immunity,and might provide new strategies to physicians for treating viral infection.