Macrophage scavenger receptor 1 controls Chikungunya virus infection through autophagy

Abstract

35Macrophage scavenger receptor 1 (MSR1) mediates the endocytosis of modified low-density 36 lipoproteins and plays an important antiviral role. However, the molecular mechanism underlying 37 MSR1 antiviral actions remains elusive. Herein, we report that MSR1 activates autophagy to 38 restrict infection of Chikungunya virus (CHIKV), an arthritogenic alphavirus that causes acute and 39 chronic crippling arthralgia. Msr1 expression was rapidly upregulated after CHIKV infection in 40 mice. Msr1 knockout mice had elevated viral loads and increased susceptibility to CHIKV arthritis 41 along with a normal type I IFN response. Induction of LC3 lipidation by CHIKV, a marker of 42 autophagy, was reduced in Msr1 -/cells. Mechanistically, MSR1 interacted with ATG12 through 43 its cytoplasmic tail and this interaction was enhanced by CHIKV nsP1 protein. MSR1 repressed 44 CHIKV replication through ATG5-ATG12-ATG16L1 and this was dependent on the FIP200-and-45 WIPI2-binding domain, but not the WD40 domain of ATG16L1. Our results elucidate an antiviral 46 role for MSR1 involving the autophagic function of ATG5-ATG12-ATG16L1. 47 48 Keywords: macrophage scavenger receptor, MSR1, Chikungunya virus, autophagy, ATG 49 50 51 Macrophage scavenger receptor 1 (MSR1) is a member of the scavenger receptor family, 52 members of which are structurally heterogeneous with little or no homology. They are grouped 53 into the same family due to their shared functional properties such as the ability to bind and 54 internalize a diverse range of self-and non-self-ligands including modified low density lipoproteins 55 (LDL), lipopolysaccharide (LPS), and lipoteichoic acid (LTA) 1 . The ligand promiscuity of these 56 scavenger receptors is probably due to their function as components of other pathogen pattern 57 recognition receptor (PRR) signaling complexes. For example, MSR1 interacts with Toll-like 58 receptor (TLR) 4 and TLR2 to promote phagocytosis of Gram-positive and negative bacteria, 59 respectively 2 , and is required for LPS-induced TLR4 signaling 3 . However, the current literature 60 about the physiological function of MSR1 in viral infections is inconsistent. MSR1 could recognize 61 extracellular viral nucleic acids, mediating their endocytosis and presenting them to TLR3/9, 62 thereby triggering a type I interferon (IFN-I) response in both infected and uninfected cells 4, 5 . 63 MSR1 limits herpes simplex virus 1 infection likely by regulating macrophage adherence in vivo 64 6 , whereas it controls adenovirus type 5-elicited hepatic inflammation and fibrosis by promoting 65 M2 macrophage polarization 7 . MSR1 could contribute to pathogenesis of murine hepatitis virus-66 induced fulminant hepatitis by activating neutrophil-mediated complement 8 . Ectopic expression 67 of MSR1 inhibited Sindbis virus A and human parainfluenza virus type 3 in STAT1 -/fibroblasts 9 , 68 suggesting an IFN-I-independent antiviral role for MSR1. These contrasting results suggest that 69 the antiviral mechanisms of MSR1 vary with viral species and disease mod...

A critical role for MSR1 in vesicular stomatitis virus infection of the central nervous system

“…Although MSR1 has proven to perform a variety of functions in homeostasis and host immunity due to its ability to recognize a diverse range of ligands (2,3), its role in viral pathogenesis remains poorly defined. MSR1 signaling may be protective against Chikungunya virus and herpes simplex virus infection (11,12), but could also contribute to hepatitis virus-induced liver damage (16). In this study, our data collectively demonstrate that of the extracellular section alone was sufficient to promote VSV infection.…”

“…We then asked if the function of MSR1during VSV infection is evolutionarily conserved. To this end, we evaluated VSV infection in a human MSR1 -/trophoblast line that was generated recently in our hands (12). Indeed, VSV-G protein level in MSR1 -/trophoblasts was much less than that in WT cells at 12 hrs after VSV infection ( Fig.…”

“…Vero cells (monkey kidney epithelial cells, # CCL-81), human trophoblasts HTR-8/SVneo (#CRL-3271) and L929 (mouse fibroblast cells, # CCL-1) were purchased from American Type Culture Collection (ATCC) (Manassas, VA20110, USA). MSR1 -/trophoblasts were generated in our previous study (12). Vero cells were grown in Corning® DMEM (Dulbecco's Modified Eagle's Medium) supplemented with 10% FBS and 1% penicillin/streptomycin.…”

“…The functions of MSR1 during viral infection may vary with virus species and disease conditions. MSR1 signaling may protect mice against lethal herpes simplex virus infection (11), activate autophagy to control Chikungunya virus infection (12) and limit replication-defective adenovirus type 5-elicited hepatic inflammation and fibrosis by promoting M2 macrophage polarization (13). MSR1 appears to function as a carrier of extracellular dsRNA of hepatitis C virus and present it to endosomal TLR3 and cytoplasmic RIG-I like receptors, resulting in an antiviral type I IFN response (14,15).…”

The role of macrophage scavenger receptor 1 (MSR1) in inflammatory disorders and cancer

“…Furthermore, it acts as a critical component of TLR3-mediated response to hepatitis C infection by endocytosis of dsRNA ( 34 ). The receptor may also mediate autophagy, contributing to the innate response against Chikungunya virus infection ( 131 ). Again, the activity of MSR1 in this area is not always protective.…”