Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

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.


  1. Rossmann, M.G., He, Y. & Kuhn, R.J. Picornavirus-receptor interactions. Trends Microbiol. 10, 324–331 (2002).

    Article  CAS  Google Scholar 

  2. Laszik, Z. et al. P-selectin glycoprotein ligand-1 is broadly expressed in cells of myeloid, lymphoid, and dendritic lineage and in some nonhematopoietic cells. Blood 88, 3010–3021 (1996).

    CAS  PubMed  Google Scholar 

  3. Sako, D. et al. Expression cloning of a functional glycoprotein ligand for P-selectin. Cell 75, 1179–1186 (1993).

    Article  CAS  Google Scholar 

  4. Somers, W.S., Tang, J., Shaw, G.D. & Camphausen, R.T. Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to SLeX and PSGL-1. Cell 103, 467–479 (2000).

    Article  CAS  Google Scholar 

  5. Shimojima, M. et al. Usage of myeloma and panning in retrovirus-mediated expression cloning. Anal. Biochem. 315, 138–140 (2003).

    Article  CAS  Google Scholar 

  6. Oberste, M.S., Maher, K., Kilpatrick, D.R. & Pallansch, M.A. Molecular evolution of the human enteroviruses: correlation of serotype with VP1 sequence and application to picornavirus classification. J. Virol. 73, 1941–1948 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Chan, L.G. et al. Deaths of children during an outbreak of hand, foot and mouth disease in Sarawak, Malaysia: clinical and pathological characteristics of the disease. Clin. Infect. Dis. 31, 678–683 (2000).

    Article  CAS  Google Scholar 

  8. Ho, M. et al. An epidemic of enterovirus 71 infection in Taiwan. N. Engl. J. Med. 341, 929–935 (1999).

    Article  CAS  Google Scholar 

  9. McMinn, P.C. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol. Rev. 26, 91–107 (2002).

    Article  CAS  Google Scholar 

  10. Lin, T.Y., Hsia, S.H., Huang, Y.C., Wu, C.T. & Chang, L.Y. Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clin. Infect. Dis. 36, 269–274 (2003).

    Article  CAS  Google Scholar 

  11. Wang, S.M. et al. Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J. Infect. Dis. 188, 564–570 (2003).

    Article  CAS  Google Scholar 

  12. Chen, L.C. et al. Enterovirus 71 infection induces Fas ligand expression and apoptosis of Jurkat cells. J. Med. Virol. 78, 780–786 (2006).

    Article  CAS  Google Scholar 

  13. Snapp, K.R. et al. A novel P-selectin glycoprotein ligand-1 monoclonal antibody recognizes an epitope within the tyrosine sulfate motif of human PSGL-1 and blocks recognition of both P- and L-selectin. Blood 91, 154–164 (1998).

    CAS  PubMed  Google Scholar 

  14. Thatte, A. et al. Binding of function-blocking mAbs to mouse and human P-selectin glycoprotein ligand-1 peptides with and without tyrosine sulfation. J. Leukoc. Biol. 72, 470–477 (2002).

    CAS  PubMed  Google Scholar 

  15. Li, F. et al. Visualization of P-selectin glycoprotein ligand-1 as a highly extended molecule and mapping of protein epitopes for monoclonal antibodies. J. Biol. Chem. 271, 6342–6348 (1996).

    Article  CAS  Google Scholar 

  16. Brown, B.A., Oberste, M.S., Alexander, J.P. Jr., Kennett, M.L. & Pallansch, M.A. Molecular epidemiology and evolution of enterovirus 71 strains isolated from 1970 to 1998. J. Virol. 73, 9969–9975 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Arita, M., Ami, Y., Wakita, T. & Shimizu, H. Cooperative effect of the attenuation determinants derived from poliovirus Sabin 1 strain is essential for attenuation of enterovirus 71 in the NOD/SCID mouse infection model. J. Virol. 82, 1787–1797 (2008).

    Article  CAS  Google Scholar 

  18. Chua, B.H., Phuektes, P., Sanders, S.A., Nicholls, P.K. & McMinn, P.C. The molecular basis of mouse adaptation by human enterovirus 71. J. Gen. Virol. 89, 1622–1632 (2008).

    Article  CAS  Google Scholar 

  19. Kung, C.M. et al. Differences in replication capacity between enterovirus 71 isolates obtained from patients with encephalitis and those obtained from patients with herpangina in Taiwan. J. Med. Virol. 79, 60–68 (2007).

    Article  CAS  Google Scholar 

  20. Kuo, R.L., Kung, S.H., Hsu, Y.Y. & Liu, W.T. Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death. J. Gen. Virol. 83, 1367–1376 (2002).

    Article  CAS  Google Scholar 

  21. Hsueh, C. et al. Acute encephalomyelitis during an outbreak of enterovirus type 71 infection in Taiwan: report of an autopsy case with pathologic, immunofluorescence and molecular studies. Mod. Pathol. 13, 1200–1205 (2000).

    Article  CAS  Google Scholar 

  22. Wong, K.T. et al. The distribution of inflammation and virus in human enterovirus 71 encephalomyelitis suggests possible viral spread by neural pathways. J. Neuropathol. Exp. Neurol. 67, 162–169 (2008).

    Article  Google Scholar 

  23. Nagata, N. et al. Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71. J. Med. Virol. 67, 207–216 (2002).

    Article  Google Scholar 

  24. Nagata, N. et al. Differential localization of neurons susceptible to enterovirus 71 and poliovirus type 1 in the central nervous system of cynomolgus monkeys after intravenous inoculation. J. Gen. Virol. 85, 2981–2989 (2004).

    Article  CAS  Google Scholar 

  25. Ong, K.C. et al. Pathologic characterization of a murine model of human enterovirus 71 encephalomyelitis. J. Neuropathol. Exp. Neurol. 67, 532–542 (2008).

    Article  Google Scholar 

  26. Chang, S.C., Lin, J.Y., Lo, L.Y.C., Li, M.L. & Shih, S.R. Diverse apoptotic pathways in enterovirus 71–infected cells. J. Neurovirol. 10, 338–349 (2004).

    Article  CAS  Google Scholar 

  27. Chen, C.S. et al. Retrograde axonal transport: a major transmission route of enterovirus 71 in mice. J. Virol. 81, 8996–9003 (2007).

    Article  CAS  Google Scholar 

  28. World Health Organization. Outbreak news. Enterovirus, China. Wkly. Epidemiol. Rec. 83, 169–170 (2008).

  29. Kitamura, T. & Morikawa, Y. Isolation of T-cell antigens by retrovirus-mediated expression cloning. Methods Mol. Biol. 134, 143–152 (2000).

    CAS  PubMed  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to Hiroyuki Shimizu.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing