Porcine Reproductive And Respiratory Syndrome Virus Infection Induces SOCS1/3 Production To Facilitate Replication

Since it was first reported in 1987,porcine reproductive and respiratory syndrome(PRRS)remains one of the most important viral diseases of pigs,causing immense economic losses in the pig industry worldwide every year.Its causative agent was PRRS virus(PRRSV).In 2006,a more serious PRRS caused by a variant highly pathogenic PRRSV(HP-PRRSV)outbroke in China.The typical immune features of PRRSV infection contain weak and aberrant innate immune responses,delayed appearance of neutralizing antibodies and inefficient cellular immune responses,which made it extremely difficult to prevent and control the disease.As key negative immune regulators of the immune system,there are few studies on the regulation of suppressors of cytokine signaling(SOCS)by PRRSV.In this study,it was shown that PRRSV significantly up-regulated SOCS1 and SOCS3 gene expression among eight SOCS family members.Thus,the thesis focuses on the molecular mechanism that underlay SOCS1 and SOCS3 induction during PRRSV infection,and exploring the mechanism of SOCS1 and SOCS3 in immunoevasion of PRRSV.In this study,it was found that SOCS1 m RNA and protein levels were significantly upregulated after PRRSV infection.And the PRRSV N protein had the ability to upregulate SOCS1 production and its nuclear localization signal-2(NLS-2)was essential for SOCS1 induction.Moreover,SOCS1 upregulation was dependent on the p38/c-Fos(activator protein 1(AP-1))and Jun N-terminal kinase(JNK)/c-Jun(AP-1)signaling pathways rather than classical type I interferons(IFNs)signaling pathways.Silencing SOCS1 significantly enhanced the expression of IFN-?,ISG56 and OAS1 a,and inhibited PRRSV replication.Overexpression of SOCS1 could inhibited poly(I:C)-triggered IFN-? expression and dramatically enhanced PRRSV replication.These results indicated that SOCS1,as an endogenous inhibitor of type I interferon,can be utilized by PRRSV to escape from host antiviral immunity.It was observed that PRRSV induced the expression of SOCS3,which was dependent on the p38/AP-1(c-Fos)signaling pathways.The phosphorylation pattern of Signal transducer and activator of transcription 3(STAT3)is altered in PRRSV infected cell.The phosphorylation level of STAT3 in PRRSV infected cells were significanlty reduced.Overexpression of porcine SOCS3 dramatically impaired the phosphorylated STAT3 expression level in a dose dependent manner and significantly enhanced PRRSV replication.The STAT3 phosphorylation level inhibited by PRRSV returned to the original level,and the PRRSV replication level was significantly reduced afther silencing SOCS3 gene.These results indicated that SOCS3 can be utilized by PRRSV to escape from host antiviral immunity.Taken together,it was reported here for the first time that PRRSV was able to elevate SOCS1 and SOCS3 expression,and the mechanism of SOCS1 impairing type I IFN signaling.All these results provide novel insights into the mechanism of immunoevasion during PRRSV infection.