Disruption of MDA5-mediated innate immune responses by the 3C proteins of coxsackievirus A16, coxsackievirus A6, and enterovirus D68

Yajuan Rui, Jiaming Su, Hong Wang, Junliang Chang, Shaohua Wang, Wenwen Zheng, Yong Cai, Wei Wei, James Gordy, Richard Bryan Markham, Wei Kong, Wenyan Zhang, Xiao Fang Yu

Research output: Contribution to journalArticle

Abstract

Coxsackievirus A16 (CV-A16), CV-A6, and enterovirus D68 (EV-D68) belong to the Picornaviridae family and are major causes of hand, foot, and mouth disease (HFMD) and pediatric respiratory disease worldwide. The biological characteristics of these viruses, especially their interplay with the host innate immune system, have not been well investigated. In this study, we discovered that the 3Cpro proteins from CV-A16, CV-A6, and EV-D68 bind melanoma differentiation-associated gene 5 (MDA5) and inhibit its interaction with MAVS. Consequently, MDA5-triggered type I interferon (IFN) signaling in the retinoic acid-inducible gene I-like receptor (RLR) pathway was blocked by the CV-A16, CV-A6, and EV-D68 3Cpro proteins. Furthermore, the CV-A16, CV-A6, and EV-D68 3Cpro proteins all cleave transforming growth factor β-activated kinase 1 (TAK1), resulting in the inhibition of NF-κB activation, a host response also critical for Toll-like receptor (TLR)-mediated signaling. Thus, our data demonstrate that circulating HFMD-associated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed novel mechanisms to subvert host innate immune responses by targeting key factors in the RLR and TLR pathways. Blocking the ability of 3Cpro proteins from diverse enteroviruses and coxsackieviruses to interfere with type I IFN induction should restore IFN antiviral function, offering a potential novel antiviral strategy.

Original languageEnglish (US)
Article numbere00546-17
JournalJournal of Virology
Volume91
Issue number13
DOIs
StatePublished - Jul 1 2017

Keywords

  • 3C protease
  • CV-A16
  • CV-A6
  • EV-D68
  • HFMD
  • Innate immune response
  • MAVS
  • MDA5
  • TAK1

ASJC Scopus subject areas

  • Immunology
  • Virology

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  • Cite this

    Rui, Y., Su, J., Wang, H., Chang, J., Wang, S., Zheng, W., Cai, Y., Wei, W., Gordy, J., Markham, R. B., Kong, W., Zhang, W., & Yu, X. F. (2017). Disruption of MDA5-mediated innate immune responses by the 3C proteins of coxsackievirus A16, coxsackievirus A6, and enterovirus D68. Journal of Virology, 91(13), [e00546-17]. https://doi.org/10.1128/JVI.00546-17