Porcine Reproductive and Respiratory Syndrome Virus nsp11 Antagonizes Broad Antiviral Effects of MCPIP1 by Inducing Interleukin-17 Expression.

Monocyte chemotactic protein-induced protein 1 (MCPIP1) is an inflammatory regulator in immune response and has broad antiviral effects by targeting viral RNA. Porcine reproductive and respiratory syndrome virus (PRRSV), a major viral pathogen in pigs, causes immune suppression leading to coinfection of swine pathogens, but the mechanisms are not fully clarified. In this study, MCPIP1 expression was found to be significantly upregulated in lungs of PRRSV-infected piglets, as well as in Marc-145 and porcine pulmonary alveolar macrophage (PAM) cells upon PRRSV stimulation. MCPIP1 overexpression significantly inhibited PRRSV replication, while MCPIP1 knockdown increased the virus titer. Various mutations in RNase functional domains of MCPIP1 impaired the inhibitory activity against PRRSV, while those in deubiquitinase domains failed to do so. MCPIP1 expression started to decrease from 60 h after PRRSV infection in PAMs. Meanwhile, infection with higher dose of PRRSV further downregulated MCPIP1, indicating the antagonizing effects from PRRSV against MCPIP1. Moreover, it was confirmed that MCPIP1 expression was downregulated in 3D4 cells with either interleukin-17 (IL-17) or nsp11 overexpression, while IL-17 inhibitor abolished the decrease of MCPIP1 caused by nsp11, indicating nsp11 employs IL-17 induction to inhibit MCPIP1. Furthermore, the PRRSV nsp11 mutant with a deficiency in IL-17 induction showed the recovered expression of MCPIP1 in infected cells, inspiring a strategy for virus attenuation. This is the first report about the role of MCPIP1 against PRRSV and the function of PRRSV nsp11 against innate immunity to facilitate virus replication via IL-17. The study not only illuminates PRRSV infection machinery but also enlightens alternative antiviral strategies, such as vaccine candidates.