Scavenger receptor B2 is a cellular receptor for enterovirus 71

Abstract

Enterovirus 71 (EV71) belongs to human enterovirus species A of the genus Enterovirus within the family Picornaviridae1. EV71, together with coxsackievirus A16 (CVA16), are most frequently associated with hand, foot and mouth disease (HFMD)1. Although HFMD is considered a mild exanthematous infection, infections involving EV71, but not CVA16, can progress to severe neurological disease, including fatal encephalitis, aseptic meningitis and acute flaccid paralysis2. In recent years, epidemic and sporadic outbreaks of neurovirulent EV71 infections have been reported in Taiwan, Malaysia, Singapore, Japan and China3,4,5,6,7. Here, we show that human scavenger receptor class B, member 2 (SCARB2, also known as lysosomal integral membrane protein II or CD36b like-2) is a receptor for EV71. EV71 binds soluble SCARB2 or cells expressing SCARB2, and the binding is inhibited by an antibody to SCARB2. Expression of human SCARB2 enables normally unsusceptible cell lines to support EV71 propagation and develop cytopathic effects. EV71 infection is hampered by the antibody to SCARB2 and soluble SCARB2. SCARB2 also supports the infection of the milder pathogen CVA16. The identification of SCARB2 as an EV71 and CVA16 receptor contributes to a better understanding of the pathogenicity of these viruses.

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Figure 1: Susceptibility of Ltr051 and Ltr246 cells to EV71.
Figure 2: SCARB2 confers susceptibility to EV71 to mouse L929 cells.
Figure 3: Interaction of SCARB2 with EV71.

References

  1. 1

    Pallansch, M. & Roos, R. Fields Virology Ch. 25, 839–893 (Lippincott Williams & Wilkins, Philadelphia, 2006).

  2. 2

    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).

  3. 3

    Qiu, J. Enterovirus 71 infection: a new threat to global public health? Lancet Neurol. 7, 868–869 (2008).

  4. 4

    Fujimoto, T. et al. Outbreak of central nervous system disease associated with hand, foot, and mouth disease in Japan during the summer of 2000: detection and molecular epidemiology of enterovirus 71. Microbiol. Immunol. 46, 621–627 (2002).

  5. 5

    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. For the Outbreak Study Group. Clin. Infect. Dis. 31, 678–683 (2000).

  6. 6

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

  7. 7

    Ahmad, K. Hand, foot, and mouth disease outbreak reported in Singapore. Lancet 356, 1338 (2000).

  8. 8

    Koike, S. et al. The poliovirus receptor protein is produced both as membrane-bound and secreted forms. EMBO J. 9, 3217–3224 (1990).

  9. 9

    Mendelsohn, C.L., Wimmer, E. & Racaniello, V.R. Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell 56, 855–865 (1989).

  10. 10

    Calvo, D., Dopazo, J. & Vega, M.A. The CD36, CLA-1 (CD36L1), and LIMPII (CD36L2) gene family: cellular distribution, chromosomal location, and genetic evolution. Genomics 25, 100–106 (1995).

  11. 11

    Eskelinen, E.L., Tanaka, Y. & Saftig, P. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 13, 137–145 (2003).

  12. 12

    Kuronita, T. et al. A role for the lysosomal membrane protein LGP85 in the biogenesis and maintenance of endosomal and lysosomal morphology. J. Cell Sci. 115, 4117–4131 (2002).

  13. 13

    Gamp, A.C. et al. LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice. Hum. Mol. Genet. 12, 631–646 (2003).

  14. 14

    Yan, J.J., Wang, J.R., Liu, C.C., Yang, H.B. & Su, I.J. An outbreak of enterovirus 71 infection in Taiwan 1998: a comprehensive pathological, virological, and molecular study on a case of fulminant encephalitis. J. Clin. Virol. 17, 13–22 (2000).

  15. 15

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

  16. 16

    Hirokawa, T., Boon-Chieng, S. & Mitaku, S. SOSUI: classification and secondary structure prediction system for membrane proteins. Bioinformatics 14, 378–379 (1998).

  17. 17

    Yanagiya, A., Jia, Q., Ohka, S., Horie, H. & Nomoto, A. Blockade of the poliovirus-induced cytopathic effect in neural cells by monoclonal antibody against poliovirus or the human poliovirus receptor. J. Virol. 79, 1523–1532 (2005).

  18. 18

    Yamayoshi, S. et al. Ebola virus matrix protein VP40 uses the COPII transport system for its intracellular transport. Cell Host Microbe 3, 168–177 (2008).

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Acknowledgements

We thank H. Shimizu (Japan National Institute of Infectious Diseases) for providing us with all viruses used in this report and critical reading of this manuscript, Y. Kawaoka (University of Tokyo) for providing us with pCAGGS-PUR, Y. Yanagi for critical reading of this manuscript and Y. Matsumoto and K. Kohyama for supporting flow cytometry. This work was supported in part by a grant-in-aid for Scientific Research (C) (20590243) from the Japan Society for the Promotion of Science and in part by a grant-in-aid for Research on Emerging and Re-emerging Infectious Diseases from the Ministry of Health, Labour and Welfare, Japan.

Author information

S.Y. designed and performed the majority of the experiments, analyzed the data and wrote the manuscript; Y.Y. constructed pSVA-EV71-GFP and established Ltr051 and Ltr246 cells; J.L. constructed pSVA-EV71; N.H., T.M. and T.T. performed microarray analysis; S.K. designed the project, assisted with the experiments, analyzed the data and wrote the manuscript.

Correspondence to Satoshi Koike.

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Supplementary Figs. 1–7, Supplementary Tables 1–3 and Supplementary Methods (PDF 1527 kb)

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Yamayoshi, S., Yamashita, Y., Li, J. et al. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med 15, 798–801 (2009). https://doi.org/10.1038/nm.1992

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