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FASEB J. 2019 Jan;33(1):942-952. doi: 10.1096/fj.201800301RRR. Epub 2018 Aug 6.

NLRP3 deficiency exacerbates enterovirus infection in mice.

Author information

1
Department of Pathology and Laboratory Medicine, James Hogg Research Center, Providence Heart and Lung Institute, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
2
Institute of Basic Theory for Traditional Chinese Medicine, China Academy of Chinese Medicine Sciences, Beijing, China.
3
Department of Vascular Surgery, RenJi Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
4
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada; and.
5
Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Abstract

The role for the NOD-like receptor (NLR) P3 inflammasome in enterovirus infection remains controversial. Available data suggest that the NLRP3 inflammasome is protective against enterovirus A71 but detrimental to the host during coxsackievirus B3 (CVB3) infection. CVB3 is a common etiologic agent associated with myocarditis and pancreatitis. Previous findings on the role of NLRP3 in CVB3 were based primarily on indirect evidence. Here, we utilized NLRP3 knockout mice as well as immune and cardiac cells to investigate the direct interplay between CVB3 infection and NLRP3 activation. We demonstrated that NLRP3 knockout mice exhibited more severe disease phenotype after CVB3 infection (significantly higher virus titers), increased myocardial, and pancreatic damage, as well as markedly impaired cardiac function compared to nontransgenic control mice. We further showed that NLRP3 activity was enhanced during early stage of CVB3 infection, as evidenced by increased gene expression and/or secretion of IL-1β and caspase-1. Finally, we demonstrated that CVB3 inactivates the NLRP3 inflammasome by degrading NLRP3 and its upstream serine/threonine-protein kinase receptor-interacting protein 1/3 via the proteolytic activity of virus-encoded proteinases. Taken together, our results reveal the functional significance of NLRP3 in host antiviral immunity against CVB3 infection and the mechanisms by which CVB3 has evolved to counteract the host defense response.-Wang, C., Fung, G., Deng, H., Jagdeo, J., Mohamud, Y., Xue, Y. C., Jan, E., Hirota, J. A., Luo, H. NLRP3 deficiency exacerbates enterovirus infection in mice.

KEYWORDS:

RIP1/RIP3; coxsackievirus; inflammasome; innate immune response

PMID:
30080445
DOI:
10.1096/fj.201800301RRR

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