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Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71

Nature Medicine volume 15, pages 794–797 (2009)Cite this article

Abstract

Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), a common febrile disease occurring mainly in young children. Although clinical manifestations of HFMD are usually mild and self limiting, a severe EV71 outbreak can lead to a diverse array of neurological diseases. Identification of the specific cellular receptors is crucial for elucidating the mechanism of early virus-host interactions and the pathogenesis of enteroviruses1. Here we identify human P-selectin glycoprotein ligand-1 (PSGL-1; CD162), a sialomucin membrane protein expressed on leukocytes that has a major role in early stages of inflammation2,3,4, as a functional receptor for EV71 using an expression cloning method by panning5. The N-terminal region of PSGL-1 binds specifically to EV71. Stable PSGL-1 expression allowed EV71 entry and replication, and development of cytopathic effects in nonsusceptible mouse L929 cells. Five out of eight EV71 strains bound soluble PSGL-1 and used intact PSGL-1 as the primary receptor for infection of Jurkat T cells. Three other EV71 strains did not use PSGL-1, suggesting the presence of strain-specific replication of EV71 in leukocytes. EV71 replicated in nonleukocyte cell lines in a PSGL-1–independent manner, indicating the presence of alternative receptor(s) for EV71. The identification of PSGL-1 as a receptor for EV71 sheds new light on a role for PSGL-1–positive leukocytes in cell tropism and pathogenesis during the course of HFMD and other EV71-mediated diseases.

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Figure 1: EV71-1095 binds human PSGL-1 expressed on 293T cells.
Figure 2: Stable expression of human PSGL-1 on mouse L929 cells permits infection by EV71-1095.
Figure 3: PSGL-1 expression and EV71-1095 replication kinetics in leukocyte and nonleukocyte cell lines.
Figure 4: EV71 strain–specific binding to PSGL-1 and replication in Jurkat T cells.

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Acknowledgements

We thank N. Takeda, S. Morikawa, Y. Matsuura, K. Moriishi, S. Koike, S. Yamayoshi and Y. Izumiya for helpful discussions; Y. Ami for technical advice regarding FACS; and N. Nishimura for preparing figures. We also thank M. Sinniah, M. Yusof (Institute for Medical Research, Malaysia) for providing EV71-SK-EV006 and KED005, N. Onnimala, Y. Pongsuwanna (National Institute of Health, Thailand) for providing EV71-02363, Y. Okuno (Osaka Prefectural Institute of Public Health) for providing EV71-C7/Osaka, K. Mizuta (Yamagata Prefectural Institute of Public Health) for providing EV71-75-Yamagata, A. Makino, Y. Tohya, H. Akashi (University of Tokyo) for providing P3U1 cells, H. Sakata (National Institute of Infectious Diseases, Japan) for providing L929 cells, and H. Shirato (National Institute of Infectious Diseases, Japan) for providing MOLT-4 and MT-2 cells. We are grateful to J. Wada for technical assistance. This work was supported by a Grant-in-Aid for Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology, Japan (Y.N.). Y.N. and H.S. were supported in part by 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.

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  1. Yoshio Tano

    Present address: Present address: Japan Poliomyelitis Research Institute, Higashimurayama-shi, Tokyo, Japan.,

Authors and Affiliations

  1. Department of Virology II, National Institute of Infectious Diseases, Musashimurayama-shi, Tokyo, Japan

    Yorihiro Nishimura, Yoshio Tano, Tatsuo Miyamura, Takaji Wakita & Hiroyuki Shimizu

  2. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan

    Masayuki Shimojima

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Contributions

Y.N. designed and performed experiments, analyzed data and wrote the paper; M.S. improved the expression cloning method; Y.T. prepared and characterized EV71-specific mAbs; and T.M. and T.W. analyzed data and wrote the paper. H.S. planned the project, designed experiments, analyzed data and wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Hiroyuki Shimizu.

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Supplementary Figs. 1–4, Supplementary Tables 1–4 and Supplementary Methods (PDF 1529 kb)

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Nishimura, Y., Shimojima, M., Tano, Y. et al. Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med 15, 794–797 (2009). https://doi.org/10.1038/nm.1961

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