Cellular receptors for enterovirus A71

Kyousuke Kobayashi,Satoshi Koike

doi:10.1186/s12929-020-0615-9

Abstract

Enterovirus 71 (EV-A71) is one of the major causative agents of hand, foot, and mouth disease. EV-A71 infection is sometimes associated with severe neurological diseases such as acute encephalitis, acute flaccid paralysis, and cardiopulmonary failure. Therefore, EV-A71 is a serious public health concern. Scavenger receptor class B, member 2 (SCARB2) is a type III transmembrane protein that belongs to the CD36 family and is a major receptor for EV-A71. SCARB2 supports attachment and internalization of the virus and initiates conformational changes that lead to uncoating of viral RNA in the cytoplasm. The three-dimensional structure of the virus-receptor complex was elucidated by cryo-electron microscopy. Two α-helices in the head domain of SCARB2 bind to the G-H loop of VP1 and the E-F loop of VP2 capsid proteins of EV-A71. Uncoating takes place in a SCARB2- and low pH-dependent manner. In addition to SCARB2, other molecules support cell surface binding of EV-A71. Heparan sulfate proteoglycans, P-selectin glycoprotein ligand-1, sialylated glycan, annexin II, vimentin, fibronectin, and prohibitin enhance viral infection by retaining the virus on the cell surface. These molecules are known as “attachment receptors” because they cannot initiate uncoating. In vivo, SCARB2 expression was observed in EV-A71 antigen-positive neurons and epithelial cells in the crypts of the palatine tonsils in patients that died of EV-A71 infection. Adult mice are not susceptible to infection by EV-A71, but transgenic mice that express human SCARB2 become susceptible to EV-A71 infection and develop neurological diseases similar to those observed in humans. Attachment receptors may also be involved in EV-A71 infection in vivo. Although heparan sulfate proteoglycans are expressed by many cultured cell lines and enhance infection by a subset of EV-A71 strains, they are not expressed by cells that express SCARB2 at high levels in vivo. Thus, heparan sulfate-positive cells merely adsorb the virus and do not contribute to replication or dissemination of the virus in vivo. In addition to these attachment receptors, cyclophilin A and human tryptophanyl aminoacyl-tRNA synthetase act as an uncoating regulator and an entry mediator that can confer susceptibility to non-susceptibile cells in the absence of SCARB2, respectively. The roles of attachment receptors and other molecules in EV-A71 pathogenesis remain to be elucidated.

Highlights

Human enteroviruses (HEVs) belonging to the genus Enterovirus within the family Picornaviridae are nonenveloped viruses with a single-stranded RNA genome of positive polarity
Viral receptors can be a primary determinant of species-specific and tissue-specific infection because enterovirus receptors mediate the initial steps of virus infection, including binding to the cell surface, internalization, and initiation of conformational changes in the virion that lead to uncoating [19]
These results suggest that nucleolin is an attachment receptor for enterovirus A71 (EV-A71)

Summary

Introduction

Human enteroviruses (HEVs) belonging to the genus Enterovirus within the family Picornaviridae are nonenveloped viruses with a single-stranded RNA genome of positive polarity. Viral receptors can be a primary determinant of species-specific and tissue-specific infection because enterovirus receptors mediate the initial steps of virus infection, including binding to the cell surface, internalization, and initiation of conformational changes in the virion that lead to uncoating [19]. The PVR is required to establish in vivo infection, its expression does not in itself determine whether specific cell types are susceptible to poliovirus infection; other factors such as innate immune responses play a role [36, 37].

Results

Conclusion