Human SCARB2-Dependent Infection by Coxsackievirus A7, A14, and A16 and Enterovirus 71

Abstract

Human enterovirus species A (HEV-A) consists of at least 16 members of different serotypes that are known to be the causative agents of hand, foot, and mouth disease (HFMD), herpangina, and other diseases, such as respiratory disease and polio-like flaccid paralysis. Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the major causative agents of HFMD. CVA5, CVA6, CVA10, and CVA12 mainly cause herpangina or are occasionally involved with sporadic cases of HFMD. We have previously shown that human scavenger receptor class B, member 2 (SCARB2) is a cellular receptor for EV71 and CVA16. Using a large number of clinical isolates of HEV-A, we explored whether all clinical isolates of EV71 and other serotypes of HEV-A infected cells via SCARB2. We tested this possibility by infecting L-SCARB2 cells, which are L929 cells expressing human SCARB2, by infecting human RD cells that had been treated with small interfering RNAs for SCARB2 and by directly binding the viruses to a soluble SCARB2 protein. We showed that all 162 clinical isolates of EV71 propagated in L-SCARB2 cells, suggesting that SCARB2 is the critical receptor common to all EV71 strains. In addition, CVA7, CVA14, and CVA16, which are most closely related to each other, also utilized SCARB2 for infection. EV71, CVA14, and CVA16 are highly associated with HFMD, and EV71 and CVA7 are occasionally associated with neurological diseases, suggesting that SCARB2 plays important roles in the development of these diseases. In contrast, another group of viruses, such as CVA2, CVA3, CVA4, CVA5, CVA6, CVA8, CVA10, and CVA12, which are relatively distant from the EV71 group, is associated mainly with herpangina. None of these clinical isolates infected via the SCARB2-dependent pathway. HEV-A viruses can be divided into at least two groups depending on the use of SCARB2, and the receptor usage plays an important role in developing the specific diseases for each group.

Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor

“…However, PSGL-1 is selectively expressed only in neutrophils, monocytes, and most lymphocytes (6). The second receptor, reported by Yamayoshi et al (9), was human SCARB2, which is expressed on most types of cells (7). EV-71 binds to the SCARB2 receptor and is then internalized through clathrin-mediated endocytosis (47,48).…”

“…PSGL-1 is a sialomucin membrane protein expressed mainly in leukocytes and was hypothesized to facilitate the viremic phase of EV-71 infection (6). The second receptor reported was the human scavenger receptor class B-2 (SCARB2), a type III double-transmembrane protein located primarily in endosomes but also expressed on the cell surface (7)(8)(9). Sialylated glycan was also reported as one of the possible receptors for EV-71 infection.…”

Cell Surface Vimentin Is an Attachment Receptor for Enterovirus 71

“…SCARB2 has been reported to play additional essential roles in the internalization and induction of virus uncoating, a step after virus attachment (57). Although numerous EV71 particles (a PB strain) were found binding to PSGL-1, this interaction did not induce conformational alterations in the cells (29). In addition, SCARB2 and PSGL-1 were reported to bind to different sites of the virion, and the affinity of the SCARB2-EV71 interaction was found to be different from that of the PSGL-1-EV71 interaction (30).…”

“…More EV71 virus binds to mouse L cells that express human PSGL-1 (L-PSGL-1 cells) than to mouse L cells that express human SCARB2 (L-SCARB2 cells) due to a higher affinity of PSGL-1 for the virus. However, EV71 could infect L-SCARB2 cells more efficiently than L-PSGL-1 cells (29,30). SCARB2 is capable of virus binding, virus internalization, and virus uncoating, while PSGL-1 is capable only of virus binding (30).…”

Antiviral activity of acid beta-glucosidase 1 on enterovirus 71, a causative agent of hand, foot and mouth disease

“…To the best of our knowledge, our finding is unique in this regard. SCARB2 supports the entry of other HFMD-causing enteroviruses [26]. The anti-viral potential of recombinant GBA1 may be applicable to other enterovirus infections.…”