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

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          Abstract

          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.

          Author Summary

          Enterovirus 71 (EV71) commonly causes mild febrile illness in children (hand, foot, and mouth disease), but some patients suffer severe neurologic disease and death. Recent outbreaks in the Asia-Pacific region have caused thousands of deaths, making EV71 a major public health concern. Some EV71 strains bind to P-selectin glycoprotein ligand-1 (PSGL-1) and infect immune cells, but others do not. We previously found that EV71 binds the PSGL-1 N-terminus, and that binding depends on tyrosine sulfation of the N-terminus, but the viral factors that control interaction with PSGL-1 have not been identified. In our present work we present evidence that a single amino acid, residue 145 of the viral capsid protein (VP1-145), determines whether a virus binds or does not bind PSGL-1, and that it functions by influencing the orientation of a nearby lysine residue (VP1-244) on the virus surface. We propose that VP1-145 controls virus tropism by changing the accessibility of the positively-charged lysine side chain of VP1-244 to the negatively charged, sulfated N-terminus of PSGL-1. Our results shed new light on virus-receptor interaction, and EV71 tropism for PSGL-1-expressing leukocytes.

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          Most cited references52

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          The SWISS-MODEL Repository and associated resources

          SWISS-MODEL Repository (http://swissmodel.expasy.org/repository/) is a database of 3D protein structure models generated by the SWISS-MODEL homology-modelling pipeline. The aim of the SWISS-MODEL Repository is to provide access to an up-to-date collection of annotated 3D protein models generated by automated homology modelling for all sequences in Swiss-Prot and for relevant models organisms. Regular updates ensure that target coverage is complete, that models are built using the most recent sequence and template structure databases, and that improvements in the underlying modelling pipeline are fully utilised. As of September 2008, the database contains 3.4 million entries for 2.7 million different protein sequences from the UniProt database. SWISS-MODEL Repository allows the users to assess the quality of the models in the database, search for alternative template structures, and to build models interactively via SWISS-MODEL Workspace (http://swissmodel.expasy.org/workspace/). Annotation of models with functional information and cross-linking with other databases such as the Protein Model Portal (http://www.proteinmodelportal.org) of the PSI Structural Genomics Knowledge Base facilitates the navigation between protein sequence and structure resources.
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            Clinical features, diagnosis, and management of enterovirus 71.

            Although poliomyelitis has been mostly eradicated worldwide, large outbreaks of the related enterovirus 71 have been seen in Asia-Pacific countries in the past 10 years. This virus mostly affects children, manifesting as hand, foot, and mouth disease, aseptic meningitis, poliomyelitis-like acute flaccid paralysis, brainstem encephalitis, and other severe systemic disorders, including especially pulmonary oedema and cardiorespiratory collapse. Clinical predictors of severe disease include high temperature and lethargy, and lumbar puncture might reveal pleocytosis. Many diagnostic tests are available, but PCR of throat swabs and vesicle fluid, if available, is among the most efficient. Features of inflammation, particularly in the anterior horns of the spinal cord, the dorsal pons, and the medulla can be clearly seen on MRI. No established antiviral treatment is available. Intravenous immunoglobulin seems to be beneficial in severe disease, perhaps through non-specific anti-inflammatory mechanisms, but has not been tested in any formal trials. Milrinone might be helpful in patients with cardiac dysfunction. Copyright © 2010 Elsevier Ltd. All rights reserved.
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              An apparently new enterovirus isolated from patients with disease of the central nervous system.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                July 2013
                July 2013
                25 July 2013
                : 9
                : 7
                : e1003511
                Affiliations
                [1 ]Department of Virology II, National Institute of Infectious Diseases, Musashimurayama-shi, Tokyo, Japan
                [2 ]Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
                [3 ]Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, Pennsylvania, United States of America
                [4 ]Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
                University of Pittsburgh, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YN HL JMB. Performed the experiments: YN. Analyzed the data: YN HL SH TW JMB HS. Contributed reagents/materials/analysis tools: YN HL SH CK JMB HS. Wrote the paper: YN HL SH JMB HS.

                Article
                PPATHOGENS-D-13-00757
                10.1371/journal.ppat.1003511
                3723564
                23935488
                02711060-5de2-4576-93da-2b641d18ac49
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 March 2013
                : 5 June 2013
                Page count
                Pages: 12
                Funding
                This work was supported by a Grant-in-Aid for Scientific Research B22390092 (to HS) and the Grant-in-Aid for Young Scientists (B) 21790452 (to YN), from the Japan Society for the Promotion of Science (JSPS) ( http://www.jsps.go.jp/j-grantsinaid/); a Grant-in-Aid for Research on Emerging and Re-emerging Infectious Diseases and a Grant-in-Aid for the Promotion of Polio Eradication, from the Ministry of Health, Labour and Welfare, Japan ( http://www.mhlw.go.jp/english/index.html) (to YN and HS); a research fellowship from the Uehara Memorial Foundation ( http://www.ueharazaidan.or.jp/) (to YN); Max Lang Junior Faculty Scholar Award and NIH K22 A179271-02 (to SH); NIH AI072490, a grant from the Foerderer Foundation, and the Plotkin Chair in Infectious Diseases at CHOP (to JMB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Clinical Immunology
                Immune Cells
                T Cells
                Infectious Diseases
                Viral Diseases
                Enterovirus Infection
                Hand, Foot, and Mouth Disease
                Infectious Diseases of the Nervous System
                Skin Infections

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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