Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy in mice

Long Yang,Harshada Ketkar,Tao Lin,Penghua Wang,Jesse Hwang,Richard A Flavell,Guang Yang,Yanlin Wang,Leilei Wang,Jianfeng Dai,Anthony T Vella,Duomeng Yang,Fuping You,Erol Fikrig,Gong Cheng,Jinzhu Ma,Shu Zhu,Tingting Geng

doi:10.1038/s42003-020-01285-6

Abstract

Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying MSR1 antiviral actions remains elusive. We report that MSR1 activates autophagy to restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in mice. Msr1 knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of autophagy, was reduced in Msr1−/− cells. Mechanistically, MSR1 interacted with ATG12 through its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1.

Highlights

Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role
MSR1 has been implicated in recognition of viral nucleic acids, activation of IFN-I4,5, macrophage adherence[6], M2 macrophage polarization[7], and activation of neutrophil-mediated complement[8], its molecular mechanism of action remains elusive
We demonstrate a critical role for MSR1 in controlling Chikungunya virus (CHIKV) pathogenesis and provide several lines of evidence showing how MSR1 participates in autophagy

Summary

Introduction

Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density lipoproteins and plays an important antiviral role. Macrophage scavenger receptor 1 (MSR1) is a member of the scavenger receptor family, members of which are structurally heterogeneous with little or no homology They are grouped into the same family due to their shared functional properties such as the ability to bind and internalize a diverse range of self- and non-self-ligands including modified low-density lipoproteins (LDL), lipopolysaccharide (LPS), and lipoteichoic acid (LTA)[1]. Ectopic expression of MSR1 inhibited Sindbis virus A and human parainfluenza virus type 3 in STAT1−/− fibroblasts[9], suggesting an IFN-I-independent antiviral role for MSR1 These contrasting results suggest that the antiviral mechanisms of MSR1 vary with viral species and disease models.

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Results

Conclusion