Activating Fc Gamma Receptor And Sialoadhesin Receptor In PAM Inhibit Innate Antiviral Immune Response In PRRSV-ADE Infection

Porcine reproductive and respiratory syndrome(PRRS)is one of the most important infectious diseases impacting swine production worldwide.PRRS is characterized by the reproductive failure in sows and the respiratory distress in piglets The etiologic agent,porcine reproductive and respiratory syndrome virus(PRRSV),is an enveloped,single-stranded,positive-sense RNA virus in the Arteriviridae family,Nidovirales.PRRSV has a very restricted tropism for swine cells of the monocyte/macrophage lineage,and the fully differentiated porcine alveolar macrophage(PAM)serves as a primary cell target for PRRSV infection.PRRSV only can infect pigs.PRRSV can cause immunosuppression and persistent infection in infected pigs.Although the infected pigs produce a rapid humoral immune response,the sub-or non-neutralizing antibody specific against PRRSV may contribute to the development of PRRS by Fc receptor-mediated antibody-dependent enhancement(ADE).ADE not only contributes to the pathogenesis of PRRSV-pesistent infection,but also has been implicated as a major obstacle to the development of efficacious vaccines for PRRSV.However,the precise mechanisms of PRRSV-ADE infection are still confusing.Therefor,a clear understanding of the event upon virus infection by the ADE pathway has become crucial for developing efficient intervention of the PRRSV infection.Porcine activating Fc gamma receptor(FcyR)(FcγRI and FcyRIII)and porcine sialodhesin(pSn)receptor have been cloned for many years.But,their roles in innate antiviral immune response to PRRSV-ADE infection have not yet been investigated.Our current studies are aim at exploring the roles of porcine activating FcγR and pSn receptor in PRRSV-ADE infection-mediated innate antiviral immune response.Our studies will enhance our understanding of the mechanisms of PRRSV-ADE infection.1.PRRSV-ADE infection suppresses innate antiviral immune response in PAM.In this study,our results showed that PRRSV infection induced the expression levels of interferon-α(IFN-α),tumor necrosis factor-α(TNF-α)and interleukine-10(IL-10)in PAM,suggesting that PRRSV infection induced innate antiviral immune response.Our results also showed that PRRSV-ADE infection in PAM inhibited the expression levels of IFN-α and TNF-α,but enhanced the expression level of IL-10,suggesting that PRRSV-ADE infection suppressed innate antiviral immune response.2.Activating FcyR and Sn receptor in PAM are involved in PRRSV-ADE infection.In this study,our results showed thar the decreasing of expression levels of FcyRI or FcγRⅢ in PAM inhibited PRRSV-ADE infetion,suggesting that porcine activating FcyR was involved in PRRSV-ADE infection.Furthermore,our results showed that the blocking of pSn1,pSn2,pSn3,pSn4,pSn5 or pSn6 domain of pSn receptor in PAM inhibited PRRSV-ADE infection,suggesting that pSn receptor was involved in PRRSV-ADE infection,and pSn1,pSn2,pSn3,pSn4,pSn5 and pSn6 domains of pSn receptor played important roles in mediating PRRSV-ADE infection.3.Activation of activating FcyR suppresses innate antiviral immune response in PAM.In this study,our results showed that specific activation of FcyRI or FcγRⅢ in PAM inhibited the expression levels of IFN-α and TNF-α,but enhanced the expression level of IL-10,suggesting that porcine activating FcyR signaling suppressed innate antiviral immune response.Our results also showed that specific activation of FcyRI or FcγRⅢ in PAM inhibited poly(I:C)-induced expression levels of IFN-α and TNF-α,but enhanced poly(I:C)-induced expression level of IL-10,suggesting that porcine activating FcyR signaling suppressed poly(I:C)-induced innate antiviral immune response.Moreover,our results showed that specific activation of FcyRⅠ or FcγRⅢ in PAM not only inhibited PRRSV infection-induced expression levels of IFN-α and TNF-α,but also enhanced PRRSV infection-induced expression level of IL-10,and facilitated PRRSV replication,suggesting that porcine activating FcyR signaling suppressed innate antiviral immune response to PRRSV infection.4.Activation of Sn receptor suppresses innate antiviral immune response in PAM.In this study,our results showed that selective activation of pSn1,pSn2,pSn3,pSn4 or pSn5 domain of pSn in PAM inhibited the expression levels of IFN-α and TNF-α,but enhanced the expression level of IL-10,suggesting that pSn signaling suppressed innate antiviral immune response,and pSn1,pSn2,pSn3,pSn4 and pSn5 domains of pSn played important roles in suppression of innate antiviral immune response.In conclusion,our present studies indicated that PRRSV-ADE infection in PAM could inhibit the expression levels of IFN-α and TNF-α and enhance the expression level of IL-10.Our studies also indicated that both FcyRⅠ,FcγRⅢ and pSn receptor in PAM could participate in PRRSV-ADE infection,and the activation signals of these receptors could inhibit the expression levels of IFN-α and TNF-α and enhance the expression level of IL-10.Thus,PRRSV-ADE infection suppressed innate antiviral immune response maybe through activating FcγR and pSn receptor in PAM,thereby enhancing PRRSV infection.