TRIM21 Restricts Coxsackievirus B3 Replication, Cardiac and Pancreatic Injury via Interacting With MAVS and Positively Regulating IRF3-Mediated Type-I Interferon Production

Hui Liu,Wei Xu,Min Li,Yahui Song

doi:10.3389/fimmu.2018.02479

Abstract

Tripartite motif-containing 21 (TRIM21) is a regulator of tissue inflammation and pro-inflammatory cytokine production, and has been implicated in negative regulation of IRF3-dependent type I interferon signaling. However, the antiviral activity of TRIM21 varies among diverse viruses and its role on regulation of type I interferon remains inconsistent in different microbial infections. Here, we investigate the potential role for TRIM21 in controlling Coxsackievirus B3 (CVB3) replication and susceptible organ pathology. We found that CVB3 infection up-regulated the expression of TRIM21 in hearts of mice and cardiomyocytes at early phase of infection. Knock-down of TRIM21 resulted in increased viral replication, while overexpression led to increased phosphorylation and dimerization of IRF3, increased IFN-β transcription and reduced viral replication in vitro. We demonstrate that TRIM21 promotes the activation of IRF3 in CVB3-infected cells via interacting with MAVS and catalyzing the K27-linked polyubiquitination of MAVS, thereby enhancing type I interferon signaling. The RING domain of ubiquitin ligase activity and PRY-SPRY domain of TRIM21 are critical for its anti-viral effect. In vivo overexpression of TRIM21 significantly protected mice against viral myocarditis by suppressing CVB3 replication and reducing cardiac inflammatory cytokine production. While TRIM21 deficient mice exhibited a decreased IFN-β production, an increased cardiac and pancreatic CVB3 replication, and aggravated pancreatic injury as well as myocarditis during acute infection. Thus, our results demonstrate TRIM21 as a positive regulator of IFN-β signaling by targeting MAVS during CVB3 infection and suggest it as a potent host defense against CVB3 infection and viral-induced injury in hearts and pancreas.

Highlights

Coxsackievirus is a single-Stranded RNA non-enveloped virus of the Enterovirus genus within Picornaviridae associated with several human and mammalian diseases, of which B3 type Coxsackievirus (CVB3) is well-identified as a major causative agent of viral myocarditis (VMC) [1, 2]
To explore the role of Tripartite motif-containing 21 (TRIM21) in Coxsackievirus B3 (CVB3) infection, first we investigate whether TRIM21 is induced in heart tissues of mice by CVB3 infection
The immunofluorescence assay showed that TRIM21 was localized in cytoplasm and CVB3 infection enhanced its expression at protein and RNA levels (Figures 1E,F).our result demonstrate that cardiac TRIM21 expression is upregulated by CVB3 infection, which may be involved in the regulation of CVB3 infection and the progression of viral myocarditis

Summary

Introduction

Coxsackievirus is a single-Stranded RNA non-enveloped virus of the Enterovirus genus within Picornaviridae associated with several human and mammalian diseases, of which B3 type Coxsackievirus (CVB3) is well-identified as a major causative agent of viral myocarditis (VMC) [1, 2]. Excessive activation of immune response triggered by virus infection maybe a major factor contributing to tissue injuries, the virus itself is critical to the progression of VMC via direct attack on cardiomyocytes [7, 8]. CVB3 RNA can be detected in the chronic stages in infected animals by 21 days post-infection, initiating the disease progression to more severe myocardial fibrosis and DCM [8, 9]. In this sense, development of novel anti-viral compounds and early intervention represents an alternative way to treat CVB3 myocarditis and related cardiomyopathy

Methods

Results

Conclusion