Metabotropic glutamate receptor subtype 2 is a cellular receptor for rabies virus.

Jinliang Wang,Zhigao Bu,Zhiyuan Wen,Renqiang Liu,Jie Luo,Chong Wang,Xijun He,Xijun Wang,Lei Shuai,Jinying Ge,Xinxin Wang,Weiye Chen,Zilong Wang,Matthias Johannes Schnell

doi:10.1371/journal.ppat.1007189

Abstract

Rabies virus (RABV) invades the central nervous system and nearly always causes fatal disease in humans. How RABV interacts with host neuron membrane receptors to become internalized and cause rabid symptoms is not yet fully understood. Here, we identified a novel receptor of RABV, which RABV uses to infect neurons. We found that metabotropic glutamate receptor subtype 2 (mGluR2), a member of the G protein-coupled receptor family that is abundant in the central nervous system, directly interacts with RABV glycoprotein to mediate virus entry. RABV infection was drastically decreased after mGluR2 siRNA knock-down in cells. Antibodies to mGluR2 blocked RABV infection in cells in vitro. Moreover, mGluR2 ectodomain soluble protein neutralized the infectivity of RABV cell-adapted strains and a street strain in cells (in vitro) and in mice (in vivo). We further found that RABV and mGluR2 are internalized into cells and transported to early and late endosomes together. These results suggest that mGluR2 is a functional cellular entry receptor for RABV. Our findings may open a door to explore and understand the neuropathogenesis of rabies.

Highlights

Rabies is an almost always fatal disease caused by rabies virus (RABV); it still kills about 60,000 people worldwide per year [1], most of whom are children in developing countries
How Rabies virus (RABV) interacts with host neuron membrane receptors to become internalized and cause rabid symptoms is not yet fully understood
We identified metabotropic glutamate receptor subtype 2 as a novel cellular RABV receptor for host cell entry. mGluR2 directly interacts with RABV G protein and both proteins are internalized together

Summary

Introduction

Rabies is an almost always fatal disease caused by rabies virus (RABV); it still kills about 60,000 people worldwide per year [1], most of whom are children in developing countries. Rabies has the highest case fatality rate among all infectious diseases, imposing a burden that is at the very least comparable to that imposed by other major zoonoses [2]. Humans are usually infected when bitten by RABV-infected dogs, and the virus invades the central nervous system (CNS) and causes rabies symptoms [3]. No treatment is proven to prevent death and the mortality rate is almost 100%. The mystery of RABV neuropathogenesis is still being unraveled despite many years of research, and this lack of information has hindered the development of therapy for rabies

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