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

Yu Pang; Yuchen Wang; Chenyu Li; Jiao Liu; Chenrui Duan; Yanrong Zhou; Liurong Fang; Shaobo Xiao

doi:10.1016/j.virol.2022.10.007

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

Virology. 2022 Dec:577:84-90. doi: 10.1016/j.virol.2022.10.007. Epub 2022 Oct 27.

Authors

Yu Pang¹, Yuchen Wang¹, Chenyu Li¹, Jiao Liu¹, Chenrui Duan¹, Yanrong Zhou¹, Liurong Fang¹, Shaobo Xiao²

Affiliations

¹ State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China.
² State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China; The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, 430070, China. Electronic address: vet@mail.hzau.edu.cn.

PMID: 36323047
DOI: 10.1016/j.virol.2022.10.007

Abstract

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.

Keywords: 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).