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

Abstract

21Macrophage scavenger receptor 1 (MSR1) plays an important role in host defense to bacterial 22 infections, M2 macrophage polarization and lipid homeostasis. However, its physiological 23 function in viral pathogenesis remains poorly defined. Herein, we report that MSR1 24 facilitates vesicular stomatitis virus (VSV) infection in the spinal cord. Msr1-deficient 25 (Msr1 -/-) mice presented reduced morbidity and mortality following lethal VSV infection, 26 along with normal viremia and antiviral innate immune responses, compared to Msr1 +/-27 littermates and wild-type mice. Msr1 expression was selectively upregulated in the spinal 28 cord, which was the predominant target of VSV infection. The viral load in the spinal cord 29 was positively correlated with Msr1 expression level and was reduced in Msr1 -/mice.30Through its extracellular domain, MSR1 interacted with VSV surface glycoprotein and 31 facilitated its cellular entry. In conclusion, our results demonstrate that MSR1 serves as a 32 cellular entry receptor for VSV and facilitates its infection specifically in the spinal cord. 33 Key words: vesicular stomatitis virus, MSR1, scavenger receptor. 34 35 36 37 38 39 40 41 3 42 Author Summary 43 As a member of Class A scavenger receptors, macrophage scavenger receptor 1 (MSR1), 44 recognizes various ligands including oxidized low-density lipoproteins (oxLDL), viruses and 45 bacterial lipopolysaccharide (LPS), therefore performs many functions in tissue homeostasis 46 and innate immunity, including pathogen clearance, lipid metabolism, macrophage 47 polarization, and pro-or anti-inflammatory responses in different disease conditions. 48 However, the physiological function of MSR1 during viral infection remains poorly 49 understood. Vesicular stomatitis virus (VSV) is a negative-sense, single-stranded RNA virus, 50 which is common in livestock (e.g. cattle, horses and swine) and produces significant 51 economic losses. VSV is also widely used as an important model virus for fundamental 52 research and vaccine development. But, the mechanism underlying VSV neurotropism is 53 largely unknown. We herein report that MSR1 serves as a cellular receptor facilitating VSV 54 infection specifically in the central nervous system. We demonstrated that MSR1 interacted 55 with VSV virions through its extracellular domain binding to VSV-G protein, and 56 overexpression of the extracellular domain alone was sufficient to promote VSV infection. 57 Our results reveal a novel function for Msr1 as a critical determinant of VSV infection 58 specifically in the spinal cord.59 60 61 62 63 4 64 Introduction 65 Macrophage scavenger receptor 1 (MSR1; also known as CD204, SCARA1 and SR-A1), a 66 member of Class A scavenger receptors, performs many functions in homeostasis and 67 immunity, including pathogen clearance, lipid metabolism and macrophage polarization [1]. 68 MSR1 recognizes a wide range of ligands including oxidized low-density lipoprotein 69 (oxLDL), endogenous proteins, beta-amyloid, lipoteichoic acid (LTA) and bacterial 70 ...