Receptors for enterovirus 71 - PubMed (original) (raw)

Receptors for enterovirus 71

Seiya Yamayoshi et al. Emerg Microbes Infect. 2014 Jul.

Abstract

Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease (HFMD). Occasionally, EV71 infection is associated with severe neurological diseases, such as acute encephalitis, acute flaccid paralysis and cardiopulmonary failure. Several molecules act as cell surface receptors that stimulate EV71 infection, including scavenger receptor B2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), sialylated glycan, heparan sulfate and annexin II (Anx2). SCARB2 plays critical roles in attachment, viral entry and uncoating, and it can facilitate efficient EV71 infection. The three-dimensional structures of the mature EV71 virion, procapsid and empty capsid, as well as the exofacial domain of SCARB2, have been elucidated. This structural information has greatly increased our understanding of the early steps of EV71 infection. Furthermore, SCARB2 plays essential roles in the development of EV71 neurological disease in vivo. Adult mice are not susceptible to infection by EV71, but transgenic mice that express human SCARB2 become susceptible to EV71 infection and develop similar neurological diseases to those found in humans. This mouse model facilitates the in vivo investigation of many issues related to EV71. PSGL-1, sialylated glycan, heparan sulfate and Anx2 are attachment receptors, which enhance viral infection by retaining the virus on the cell surface. These molecules also contribute to viral infection in vitro either by interacting with SCARB2 or independently of SCARB2. However, the cooperative effects of these receptors, and their contribution to EV71 pathogenicity in vivo, remain to be elucidated.

Keywords: SCARB2; enterovirus 71; hand, foot and mouth disease; neurological disease.

PubMed Disclaimer

Figures

Figure 1

Figure 1

Schematic showing the process of enterovirus uncoating. The mature virion (left) comprises 60 copies each of VP1, VP2, VP3 and VP4, and agenomic RNA. The virion is captured by its cognate receptor on the target cell surface and then internalized. The Ig-like domain in PVR, CAR and ICAM-1 binds to the canyon of the virus and induces a conformational change. The A-particle (middle) comprises 60 copies each of VP1, VP2 and VP3, together with the genomic RNA. The A-particle increases in diameter by approximately 4% and has a large hole near the two- and three-fold axes. The N-terminus of VP1 is externalized and anchors the virus to the membrane, where extruded VP4s associate to form a channel through the membrane. The viral RNA is then released from the hole close to the two-fold axis and enters the cell cytoplasm. Minor group human rhinoviruses bind to LDLR family members and the conformational change of the virionis induced by the low endosomal pH. The resulting empty capsid (right) comprises 60 copies each of VP1, VP2 and VP3. CAR, coxsackie-adenovirus receptor; ICAM-1, intercellular adhesion molecule-1; LDLR, low-density lipoprotein receptor.

Figure 2

Figure 2

EV71 infection mediated by SCARB2 and other receptors. SCARB2 delivers β-GC from the ER to the lysosomes under physiological conditions. SCARB2 is abundant in the lysosomal and endosomal compartments, and it also shuttles to the plasma membrane where it encounters EV71. After binding the virus on the cell surface, the virus–receptor complex is internalized via the clathrin-mediated endocytosis pathway. In the endosome or lysosome, where the pH is low, the virus initiates a conformational change that leads to uncoating. PSGL-1 can bind EV71 and internalize via caveolin-mediated endocytosis, but PSGL-1 cannot initiate uncoating. Anx2, heparan sulfate, and sialylated glycans can also bind EV71. However, the mechanism of internalization and uncoating is unknown. They may deliver EV71 to SCARB2 or they may establish infections via their own mechanisms. β-GC, β-glucocerebrosidase; ER, endoplasmic reticulum.

Figure 3

Figure 3

Crystal structure of SCARB2. The crystal structure of the SCARB2 ectodomain (PDB: 4F7B) was determined by X-ray diffraction. The important amino acid region responsible for binding to EV71 (amino acids 142–204) is shown in yellow. Arrows represent β-strands and tubes represent α-helices. Black, red and blue sticks and balls represent the carbohydrate chains.

References

    1. Oberste MS, Jiang X, Maher K, Nix WA, Jiang B. The complete genome sequences for three simian enteroviruses isolated from captive primates. Arch Virol. 2008;153:2117–2122. - PubMed
    1. Oberste MS, Maher K, Pallansch MA. Complete genome sequences for nine simian enteroviruses. J Gen Virol. 2007;88:3360–3372. - PubMed
    1. Pallansch M, Roos R.Enteroviruses. polioviruses, coxsackieviruses, echoviruses, and newer enterovirusesIn: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE (ed.)Fields Virology5th ed. Philadelphia, PA; Lippincott Williams & Wilkins, 2007; 839–893.
    1. Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929–935. - PubMed
    1. Schmidt NJ, Lennette EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis. 1974;129:304–309. - PubMed

LinkOut - more resources