Activating FcγRI inhibits RIG-I-mediated host antiviral innate immunity by FGR during PRRSV-ADE infection.

Abstract

Currently, the antibody-dependent enhancement (ADE) effect has been a pivotal factor in the persistent infection of pigs with porcine reproductive and respiratory syndrome virus (PRRSV) and a major hurdle in developing safe and effective vaccines. Therefore, elucidating the molecular mechanisms of ADE in PRRSV infection is crucial. This study assessed the impact of Fc gamma receptor I (FcγRI), Fc epsilon receptor gamma chain (FCER1G), and FGR on the host's antiviral innate immune response during PRRSV-ADE infection in vitro. Our results revealed that the expressions of RIG-I, TBK-1, IRF-3, STAT-1, and STAT-2 were markedly inhibited in porcine alveolar macrophages (PAMs) via ADE. Furthermore, the production of IFN-α, ISG15, ISG56, OAS1, OAS2, Mx1, and RSAD2 were dramatically decreased during PRRSV-ADE infection. Additionally, gene knockdown studies indicated that PRRSV-ADE infection upregulates FGR expression by activating FcγRI. Moreover, knocking down endogenous FcγRI, FCER1G, or FGR alleviated the inhibitory effect of PRRSV-ADE infection on the RIG-I-mediated antiviral innate immune response in PAMs. Thus, our findings demonstrate that activation FcγRI could suppress RIG-I-mediated antiviral innate immune response through FGR during PRRSV-ADE infection, thereby facilitating viral replication. These insights enhance our understanding of the molecular mechanism of underlying intrinsic ADE (iADE) and could contribute to the design of novel PRRSV vaccine.