Cellular Receptors for Human Enterovirus Species A

Nishimura, Yorihiro; Shimizu, Hiroyuki

doi:10.3389/fmicb.2012.00105

Cited by 37 publications

(24 citation statements)

References 48 publications

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“…The EV71 was often found in the older groups in the survivors, while the other EV was the major cause in the <2 years old group. This situation may be caused by the number of the receptors and the affinity of EV71 and other EV in the different age groups, along with the immune level . However, EV and EV71 have no difference between female and male cases among the survivors and deaths groups, different from Fischer et al .…”

Section: Discussionmentioning

confidence: 99%

Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014

et al. 2015

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This study aimed to analyze the epidemiology and virology of fatal and nonfatal hand, foot, and mouth disease (HFMD) cases in Mainland China. A total of 10,714,237 survivors and 3046 deaths were reported from 2008 to 2014 June, with a case fatality rate of 0.03%. The morbidity of the survivors increased from 37.6/100,000 in 2008 to 139.6/100,000 in 2013 and peaked in 2012 at 166.8/100,000. However, the mortality varied around 0.03-0.04/100,000 across the time. Most of the survivors were distributed in the southern and eastern China, predominantly in the Guangxi and Hainan Province, whereas deaths were dominant in southern (Guangxi) and southwestern (Guizhou) China. The two groups showed similar seasonal fluctuations from 2008 to 2014, peaking in spring and early summer. Of the total cases, 93.97% were children less than 5 years of age, with those ≤ 2 years old accounting for 60.08% versus 84.02% in the survivor and death groups, respectively. Boys were at higher risk of infection than girls in both groups. Five years of virological surveillance showed that 43.73%, 22.04%, and 34.22% of HFMD cases were due to EV71, CoxA16 and other enteroviruses, respectively. EV71 was encountered in most deaths, with no substantial effect of age, gender, month, and year on incidence. Subgenotype C4a was the prevalent EV71 strain in Mainland China, with no significant difference in the VP1 gene related to virulence between the two groups. In conclusion, based on the largest population study, fatal and nonfatal HFMD cases, mainly caused by C4a of EV71, are circulating in Mainland China with a low-cause fatality rate.

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Section: Discussionmentioning

confidence: 99%

Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014

et al. 2015

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“…EV71 isolates use at least two transmembrane proteins as receptors (reviewed in [17], [18]). Scavenger receptor class B, member 2 (SCARB2), originally identified as an EV71 receptor on rhabdomyosarcoma (RD) cells [14], is expressed on a broad variety of cell types.…”

Section: Introductionmentioning

confidence: 99%

Enterovirus 71 Binding to PSGL-1 on Leukocytes: VP1-145 Acts as a Molecular Switch to Control Receptor Interaction

et al. 2013

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Some strains of enterovirus 71 (EV71), but not others, infect leukocytes by binding to a specific receptor molecule: the P-selectin glycoprotein ligand-1 (PSGL-1). We find that a single amino acid residue within the capsid protein VP1 determines whether EV71 binds to PSGL-1. Examination of capsid sequences of representative EV71 strains revealed that the PSGL-1-binding viruses had either a G or a Q at residue 145 within the capsid protein VP1 (VP1-145G or Q), whereas PSGL-1-nonbinding viruses had VP1-145E. Using site-directed mutagenesis we found that PSGL-1-binding strains lost their capacity to bind when VP1-145G/Q was replaced by E; conversely, nonbinding strains gained the capacity to bind PSGL-1 when VP1-145E was replaced with either G or Q. Viruses with G/Q at VP1-145 productively infected a leukocyte cell line, Jurkat T-cells, whereas viruses with E at this position did not. We previously reported that EV71 binds to the N-terminal region of PSGL-1, and that binding depends on sulfated tyrosine residues within this region. We speculated that binding depends on interaction between negatively charged sulfate groups and positively charged basic residues in the virus capsid. VP1-145 on the virus surface is in close proximity to conserved lysine residues at VP1-242 and VP1-244. Comparison of recently published crystal structures of EV71 isolates with either Q or E at VP1-145 revealed that VP1-145 controls the orientation of the lysine side-chain of VP1-244: with VP1-145Q the lysine side chain faces outward, but with VP1-145E, the lysine side chain is turned toward the virus surface. Mutation of VP1-244 abolished virus binding to PSGL-1, and mutation of VP1-242 greatly reduced binding. We propose that conserved lysine residues on the virus surface are responsible for interaction with sulfated tyrosine residues at the PSGL-1 N-terminus, and that VP1-145 acts as a switch, controlling PSGL-1 binding by modulating the exposure of VP1-244K.

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“…SCARB2 not only facilitates the infection of EV71 but is also involved in virus internalization and the viral RNA uncoating of EV71 (16). Unlike SCARB2, PSGL-1 mediates the infection of some, but not all, EV71 strains or genotypes (7,17). In addition, PSGL-1 participates in EV71 virus binding but not virus entry and viral RNA release (16).…”

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confidence: 99%

Cell Surface Nucleolin Facilitates Enterovirus 71 Binding and Infection

Wang

Huang

et al. 2015

J Virol

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Because the pathogenesis of enterovirus 71 (EV71) remains mostly ambiguous, identifying the factors that mediate viral binding and entry to host cells is indispensable to ultimately uncover the mechanisms that underlie virus infection and pathogenesis. Despite the identification of several receptors/attachment molecules for EV71, the binding, entry, and infection mechanisms of EV71 remain unclear. Herein, we employed glycoproteomic approaches to identify human nucleolin as a novel binding receptor for EV71. Glycoproteins purified by lectin chromatography from the membrane extraction of human cells were treated with sialidase, followed by immunoprecipitation with EV71 particles. Among the 16 proteins identified by tandem mass spectrometry analysis, cell surface nucleolin attracted our attention. We found that EV71 interacted directly with nucleolin via the VP1 capsid protein and that an antinucleolin antibody reduced the binding of EV71 to human cells. In addition, the knockdown of cell surface nucleolin decreased EV71 binding, infection, and production in human cells. Furthermore, the expression of human nucleolin on the cell surface of a mouse cell line increased EV71 binding and conferred EV71 infection and production in the cells. These results strongly indicate that human nucleolin can mediate EV71 binding to and infection of cells. Our findings also demonstrate that the use of glycoproteomic approaches is a reliable methodology to discover novel receptors for pathogens. IMPORTANCEOutbreaks of EV71 have been reported in Asia-Pacific countries and have caused thousands of deaths in young children during the last 2 decades. The discovery of new EV71-interacting molecules to understand the infection mechanism has become an emergent issue. Hence, this study uses glycoproteomic approaches to comprehensively investigate the EV71-interacting glycoproteins. Several EV71-interacting glycoproteins are identified, and the role of cell surface nucleolin in mediating the attachment and entry of EV71 is characterized and validated. Our findings not only indicate a novel target for uncovering the EV71 infection mechanism and anti-EV71 drug discovery but also provide a new strategy for virus receptor identification.

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Cellular Receptors for Human Enterovirus Species A

Cited by 37 publications

References 48 publications

Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014

Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014

Enterovirus 71 Binding to PSGL-1 on Leukocytes: VP1-145 Acts as a Molecular Switch to Control Receptor Interaction

Cell Surface Nucleolin Facilitates Enterovirus 71 Binding and Infection

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