Inhibition of antiviral innate immunity by foot-and-mouth disease virus Lpro through interaction with the n-terminal domain of swine RNase L

Chao Sui, Dandan Jiang, Xiangju Wu, Sidang Liu, Feng Li, Li Pan, Xiaoyan Cong, Juntong Li, Dongwan Yoo, Daniel L. Rock, Laura C. Miller, Changhee Lee, Yijun Du, Jing Qi

Research output: Contribution to journalArticlepeer-review

Abstract

Foot-and-mouth disease virus (FMDV) is the pathogen of foot-and-mouth disease (FMD), which is a highly contagious disease in cloven-hoofed animals. To survive in the host, FMDV has evolved multiple strategies to antagonize host innate immune responses. In this study, we showed that the leader protease (Lpro) of FMDV, a papain-like proteinase, promoted viral replication by evading the antiviral interferon response through counteracting the 29,59-oligoadenylate synthetase (OAS)/RNase L system. Specifically, we observed that the titers of Lpro deletion virus were significantly lower than those of wild-type FMDV (FMDV-WT) in cultured cells. Our mechanistic studies demonstrated that Lpro interfered with the OAS/RNase L pathway by interacting with the N-terminal domain of swine RNase L (sRNase L). Remarkably, Lpro of FMDV exhibited species-specific binding to RNase L in that the interaction was observed only in swine cells, not human, monkey, or canine cells. Lastly, we presented evidence that by interacting with sRNase L, FMDV Lpro inhibited cellular apoptosis. Taken together, these results demonstrate a novel mechanism that Lpro utilizes to escape the OAS/RNase L-mediated antiviral defense pathway. IMPORTANCE FMDV is a picornavirus that causes a significant disease in agricultural animals. FMDV has developed diverse strategies to escape the host interferon response. Here, we show that Lpro of FMDV antagonizes the OAS/RNase L pathway, an important interferon effector pathway, by interacting with the N-terminal domain of sRNase L. Interestingly, such a virus-host interaction is species-specific because the interaction is detected only in swine cells, not in human, monkey, or canine cells. Furthermore, Lpro inhibits apoptosis through interacting with sRNase L. This study demonstrates a novel mechanism by which FMDV has evolved to inhibit host innate immune responses.

Original languageEnglish (US)
Article numbere00361-21
JournalJournal of virology
Volume95
Issue number15
DOIs
StatePublished - Jul 2021

Keywords

  • Antagonistic mechanism
  • FMDV
  • Foot-and-mouth disease virus
  • ISGs
  • L
  • RNase L

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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