Itaconate derivative 4-OI inhibits PRRSV proliferation and associated inflammatory response

• Published in: Virology (New York, N.Y.) N.Y.), 2022-12, Vol.577, p.84-90
• Main Authors: Pang, Yu, Wang, Yuchen, Li, Chenyu, Liu, Jiao, Duan, Chenrui, Zhou, Yanrong, Fang, Liurong, Xiao, Shaobo
• Format: Article
• Language: English
• Subjects: 4-octyl itaconate (4-OI); Immunoresponsive gene 1 (IRG1); Itaconate; Nuclear factor-erythroid 2-related factor 2 (Nrf2); Porcine reproductive and respiratory syndrome virus (PRRSV)
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2022.10.007

Itaconate, a metabolite of the tricarboxylic acid (TCA) cycle produced by immunoresponsive gene 1 (IRG1) via catalyzation of cis-aconitate, plays important roles in metabolism and immunity. Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has devastated the swine industry worldwide for over 30 years. Here, we found that 4-octyl itaconate (4-OI), a cell-permeable itaconate derivative, dose-dependently inhibited PRRSV proliferation by interfering with viral attachment, replication, and release. Furthermore, 4-OI suppressed the PRRSV-induced inflammatory response by enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Interestingly, PRRSV infection caused a reduction in itaconate abundance and simultaneously led to an accumulation of cis-aconitate, the upstream metabolite of itaconate, and both of these effects were accomplished by downregulating IRG1 expression. Taken together, these results demonstrate that 4-OI not only inhibits PRRSV replication but also suppresses PRRSV-induced inflammatory responses, indicating that 4-OI is a promising drug candidate for combating PRRSV. •4-OI limits PRRSV growth by inhibiting viral attachment, replication and release.•4-OI strongly impedes inflammatory response to PRRSV infection.•PRRSV infection affects the itaconate-IRG1-cis-aconitate axis.•The optimized replication of PRRSV depends on cis-aconitate.