Study Of Human EV-D68 Induces Autophagy Negative Regulation IRF7 Associated Immune Response And Proteasome Inhibitor PS-341 Antiviral

Human Enterovirus D68(EV-D68),which belongs to the Picornaviridae family Enterovirus genus,is a single-stranded positive-sense RNA virus.EV-D68 can be classified into four species according to serotypes: A,B,C,and D.Enterovirus D68(EV-D68)belongs to group D within EV(D70,D94,D111,D68,D120).According to epidemiological data,EV-D68 are associated with serious respiratory diseases,such as respiratory infections,bronchitis and pneumonia and EV-D68 is especially the major cause of severe neurological complications,such as acute flaccid paralysis and intracranial nerve dysfunction.Study on this pathogenic mechanism of the emerging virus is rare,and there is no effective vaccine or antiviral drug is currently available for the treatment of this infection.This study focused on EV-D68 induced autophagy to negative regulated IRF7-mediated type I Interferon pathway and the antiviral activity of PS-341.This study found that EV-D68 Fermon strain,UV-inactivated EV-D68 and structural protein can induce autophagy,and further participate in down-regulate type I interferon expression probably.With the study of the structural proteins,we first discovered new mechanism.The structural protein VP3 supress the expression of Se V-induced IFN-? to escapes the natural immunity.By screening multiple immune factors in the interferon pathway,the target protein IRF7 in the host was successfully founded.With systematic experiments,it was found that VP3 can inhibit the activation of IRF7 for further inhibite IRF7 phosphorylation,nuclear import and TRAF6-mediated K63 ubiquitination to regulate of interferon.At the same time,by constructing the IRF7 truncation mutants,it was confirmed that the inhibitory domain(ID)is the binding region with VP3.According to these studies,we further found that the VP3 protein of EV71 and CA16 viruses can bind with IRF7 to inhibite type I innate immunity in host,which indicated that the enterovirus VP3 antagonizes host natural immunity with a broad spectrum.Research on antiviral drugs,we determined that PS-341 inhibits EV-D68 gene replication and assembly within safe concentration,but without effect on adsorption,entry,and release.Ac-YVAD-CHO,an inhibitor of apoptosis,can attenuate the inhibition of viral proliferation by PS-341,which suggesting that PS-341 is likely to inhibit viral proliferation by inducing apoptosis.Besides,PS-341 can also inhibit the replication of CVB3,which indicating that PS-341 may be used as a preventive and therapeutic drug against enterovirus in clinic.In this study,we explored the regulation mechanism of EV-D68 virus particle and structural protein VP3 induce autophagy to negative regulate type I interferon natural immune,further extended the mechanism of EV-D68 escape the host innate immune interferon.With analyzing the antiviral mechanism of PS-341 against enterovirus,we provides a new basis for the development and clinical application of PS-341 as a new antiviral drug for enterovirus.