Nuclear factor IC promoting porcine reproductive and respiratory syndrome virus (PRRSV) replication and suppressing type I interferon transcription

Porcine reproductive and respiratory syndrome virus (PRRSV) is the most rapidly mutating RNA virus and causes billions of dollars in annual losses for the global pig industry, making it a persistent threat to swine health. Identifying and targeting host proteins involved in PRRSV replication could provide novel and conserved targets for anti-PRRSV drug development. The NFI family proteins (NFIA, NFIB, NFIC, and NFIX) are known regulators of DNA virus and retrovirus replication. Given that our previous work identified NFIA and NFIB as inhibitors of PRRSV, this study aimed to determine whether NFIC also modulated PRRSV replication. Firstly, ectopic expression of NFIC significantly enhanced PRRSV replication, while siRNA-mediated knockdown of NFIC resulted in a marked reduction in viral titers in MARC-145 cells. Furthermore, PRRSV infection upregulated NFIC expression, suggesting a coordinated mechanism by which the virus hijacked host factors for its replication. Mechanistically, we demonstrated that NFIC disrupted type I interferon (IFN-I) transcription by blocking the nuclear translocation of phosphorylated interferon regulatory factor 3 (pIRF3), an essential transcription factor for IFN-I induction. In conclusion, PRRSV infection upregulated NFIC expression, which in turn facilitated PRRSV replication and suppressed IFN-I transcription. Given that PRRSV suppressed IFN-I transcription and recombinant IFN-I could clear PRRSV, NFIC could be as a potential target for anti-PRRSV drug development in future studies.