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Tetraspanins on the surface of Schistosoma mansoni are protective antigens against schistosomiasis


Schistosomes are blood-dwelling flukes that infect 200 million people worldwide and are responsible for hundreds of thousands of deaths annually1. Using a signal sequence trap, we cloned from Schistosoma mansoni two cDNAs, Sm-tsp-1 and Sm-tsp-2, encoding the tetraspanin (TSP) integral membrane proteins TSP-1 and TSP-2. We raised antibodies to recombinant TSP fusion proteins and showed that both proteins are exposed on the surface of S. mansoni. Recombinant TSP-2, but not TSP-1, is strongly recognized by IgG1 and IgG3 (but not IgE) from naturally resistant individuals but is not recognized by IgG from chronically infected or unexposed individuals. Vaccination of mice with the recombinant proteins followed by challenge infection with S. mansoni resulted in reductions of 57% and 64% (TSP-2) and 34% and 52% (TSP-1) for mean adult worm burdens and liver egg burdens, respectively, over two independent trials. Fecal egg counts were reduced by 65–69% in both test groups. TSP-2 in particular provided protection in excess of the 40% benchmark set by the World Health Organization for progression of schistosome vaccine antigens into clinical trials. When coupled with its selective recognition by naturally resistant people, TSP-2 seems to be an effective vaccine antigen against S. mansoni.

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Figure 1: TSP-1 and TSP-2 are expressed in the outer tegument of adult S. mansoni.
Figure 2: Individuals who are putatively resistant to S. mansoni selectively recognize TSP-2, but chronically infected individuals do not.

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  1. World Health Organization. Prevention and control of schistosomiasis and soil-transmitted helminthiasis: report of a WHO expert committee (World Health Organization, Geneva, 2002).

  2. King, C.H., Dickman, K. & Tisch, D.J. Reassessment of the cost of chronic helmintic infection: a meta-analysis of disability-related outcomes in endemic schistosomiasis. Lancet 365, 1561–1569 (2005).

    Article  Google Scholar 

  3. Bergquist, N.R., Leonardo, L.R. & Mitchell, G.F. Vaccine-linked chemotherapy: can schistosomiasis control benefit from an integrated approach? Trends Parasitol. 21, 112–117 (2005).

    Article  CAS  Google Scholar 

  4. Minard, P., Dean, D.A., Jacobson, R.H., Vannier, W.E. & Murrell, K.D. Immunization of mice with cobalt-60 irradiated Schistosoma mansoni cercariae. Am. J. Trop. Med. Hyg. 27, 76–86 (1978).

    Article  CAS  Google Scholar 

  5. Stek, M.F., Minard, P., Dean, D.A. & Hall, J.E. Immunization of baboons with Schistosoma mansoni cercariae attenuated by gamma irradiation. Science 212, 1518–1520 (1981).

    Article  CAS  Google Scholar 

  6. Bergquist, N.R. & Colley, D.G. Schistosomiasis vaccines: research to development. Parasitol. Today 14, 99–104 (1998).

    Article  CAS  Google Scholar 

  7. Verjovski-Almeida, S. et al. Transcriptome analysis of the acoelomate human parasite Schistosoma mansoni. Nat. Genet. 35, 148–157 (2003).

    Article  Google Scholar 

  8. El-Sayed, N.M., Bartholomeu, D., Ivens, A., Johnston, D.A. & LoVerde, P.T. Advances in schistosome genomics. Trends Parasitol. 20, 154–157 (2004).

    Article  CAS  Google Scholar 

  9. Pearce, E.J. & MacDonald, A.S. The immunobiology of schistosomiasis. Nat. Rev. Immunol. 2, 499–511 (2002).

    Article  CAS  Google Scholar 

  10. Jones, M.K., Gobert, G.N., Zhang, L., Sunderland, P. & McManus, D.P. The cytoskeleton and motor proteins of human schistosomes and their roles in surface maintenance and host-parasite interactions. Bioessays 26, 752–765 (2004).

    Article  CAS  Google Scholar 

  11. Smyth, D. et al. Isolation of cDNAs encoding secreted and transmembrane proteins from Schistosoma mansoni by a signal sequence trap method. Infect. Immun. 71, 2548–2554 (2003).

    Article  CAS  Google Scholar 

  12. Levy, S. & Shoham, T. The tetraspanin web modulates immune-signalling complexes. Nat. Rev. Immunol. 5, 136–148 (2005).

    Article  CAS  Google Scholar 

  13. van Balkom, B.W. et al. Mass spectrometric analysis of the Schistosoma mansoni tegumental sub-proteome. J. Proteome Res. 4, 958–966 (2005).

    Article  CAS  Google Scholar 

  14. Braschi, S. & Wilson, R.A. Proteins exposed at the adult schistosome surface revealed by biotinylation. Mol. Cell. Proteomics (2005).

  15. Correa-Oliveira, R. et al. The human immune response to defined immunogens of Schistosoma mansoni: elevated antibody levels to paramyosin in stool-negative individuals from two endemic areas in Brazil. Trans. R. Soc. Trop. Med. Hyg. 83, 798–804 (1989).

    Article  CAS  Google Scholar 

  16. Correa-Oliveira, R., Caldas, I.R. & Gazzinelli, G. Natural versus drug-induced resistance in Schistosoma mansoni infection. Parasitol. Today 16, 397–399 (2000).

    Article  CAS  Google Scholar 

  17. Viana, I.R. et al. Comparison of antibody isotype responses to Schistosoma mansoni antigens by infected and putative resistant individuals living in an endemic area. Parasite Immunol. 17, 297–304 (1995).

    Article  CAS  Google Scholar 

  18. Viana, I.R. et al. Interferon-gamma production by peripheral blood mononuclear cells from residents of an area endemic for Schistosoma mansoni. Trans. R. Soc. Trop. Med. Hyg. 88, 466–470 (1994).

    Article  CAS  Google Scholar 

  19. Hoffmann, K.F., Wynn, T.A. & Dunne, D.W. Cytokine-mediated host responses during schistosome infections; walking the fine line between immunological control and immunopathology. Adv. Parasitol. 52, 265–307 (2002).

    Article  Google Scholar 

  20. Ribeiro de Jesus, A. et al. Human immune responses to Schistosoma mansoni vaccine candidate antigens. Infect. Immun. 68, 2797–2803 (2000).

    Article  CAS  Google Scholar 

  21. Al-Sherbiny, M. et al. In vitro cellular and humoral responses to Schistosoma mansoni vaccine candidate antigens. Acta Trop. 88, 117–130 (2003).

    Article  CAS  Google Scholar 

  22. Brito, C.F., Caldas, I.R., Coura Filho, P., Correa-Oliveira, R. & Oliveira, S.C. CD4+ T cells of schistosomiasis naturally resistant individuals living in an endemic area produce interferon-gamma and tumour necrosis factor-alpha in response to the recombinant 14KDA Schistosoma mansoni fatty acid-binding protein. Scand. J. Immunol. 51, 595–601 (2000).

    Article  CAS  Google Scholar 

  23. James, S.L. & Sher, A. Mechanisms of protective immunity against Schistosoma mansoni infection in mice vaccinated with irradiated cercariae III. Identification of a mouse strain, P/N, that fails to respond to vaccination. Parasite Immunol. 5, 567–575 (1983).

    Article  CAS  Google Scholar 

  24. James, S.L., Labine, M. & Sher, A. Mechanisms of protective immunity against Schistosoma mansoni infection in mice vaccinated with irradiated cercariae. I. Analysis of antibody and T-lymphocyte responses in mouse strains developing differing levels of immunity. Cell. Immunol. 65, 75–83 (1981).

    Article  CAS  Google Scholar 

  25. Lewis, F.A. & Wilson, E.M. Strain differences in lymphocyte responses and in vitro suppressor cell induction between Schistosoma mansoni-infected C57BL/6 and CBA mice. Infect. Immun. 32, 260–267 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Williams, G.M. et al. Mathematical modelling of schistosomiasis japonica: comparison of control strategies in the People's Republic of China. Acta Trop. 82, 253–262 (2002).

    Article  Google Scholar 

  27. Harn, D.A., Mitsuyama, M., Huguenel, E.D. & David, J.R. Schistosoma mansoni: detection by monoclonal antibody of a 22,000-dalton surface membrane antigen which may be blocked by host molecules on lung stage parasites. J. Immunol. 135, 2115–2120 (1985).

    CAS  PubMed  Google Scholar 

  28. Sher, A., Hall, B.F. & Vadas, M.A. Acquisition of murine major histocompatibility complex gene products by schistosomula of Schistosoma mansoni. J. Exp. Med. 148, 46–57 (1978).

    Article  CAS  Google Scholar 

  29. Loukas, A., Jones, M.K., King, L.T., Brindley, P.J. & McManus, D.P. Receptor for Fc on the surfaces of schistosomes. Infect. Immun. 69, 3646–3651 (2001).

    Article  CAS  Google Scholar 

  30. Silva, E.E., Clarke, M.W. & Podesta, R.B. Characterization of a C3 receptor on the envelope of Schistosoma mansoni. J. Immunol. 151, 7057–7066 (1993).

    CAS  PubMed  Google Scholar 

  31. Bethony, J. et al. Exposure to Schistosoma mansoni infection in a rural area in Brazil. III: Household aggregation of water-contact behaviour. Trop. Med. Int. Health 9, 381–389 (2004).

    Article  Google Scholar 

  32. Bethony, J. et al. Exposure to Schistosoma mansoni infection in a rural area in Brazil. II: Household risk factors. Trop. Med. Int. Health 6, 136–145 (2001).

    Article  CAS  Google Scholar 

  33. Gazzinelli, A. et al. Exposure to Schistosoma mansoni infection in a rural area of Brazil. I: Water contact. Trop. Med. Int. Health 6, 126–135 (2001).

    Article  CAS  Google Scholar 

  34. Kloos, H., Passos, L.K., Loverde, P., Oliveira, R.C. & Gazzinelli, A. Distribution and Schistosoma mansoni infection of Biomphalaria glabrata in different habitats in a rural area in the Jequitinhonha Valley, Minas Gerais, Brazil: environmental and epidemiological aspects. Mem. Inst. Oswaldo Cruz 99, 673–681 (2004).

    Article  Google Scholar 

  35. Kloos, H. et al. Combined methods for the study of water contact behavior in a rural schistosomiasis-endemic area in Brazil. Acta Trop. 97, 31–41 (2006).

    Article  Google Scholar 

  36. Bethony, J. et al. Familial resemblance in humoral immune response to defined and crude Schistosoma mansoni antigens in an endemic area in Brazil. J. Infect. Dis. 180, 1665–1673 (1999).

    Article  CAS  Google Scholar 

  37. Bethony, J. et al. Additive host genetic factors influence fecal egg excretion rates during Schistosoma mansoni infection in a rural area in Brazil. Am. J. Trop. Med. Hyg. 67, 336–343 (2002).

    Article  CAS  Google Scholar 

  38. Harn, D.A., Mitsuyama, M. & David, J.R. Schistosoma mansoni: anti-egg monoclonal antibodies protect against cercarial challenge in vivo. J. Exp. Med. 159, 1371–1387 (1984).

    Article  CAS  Google Scholar 

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We thank M. Smout for assistance with figure preparations, W. Schroeder for technical assistance and D. Diemert and P. Hotez for comments on the manuscript and discussions. This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC) and The Wellcome Trust. A.L. is the recipi of an R. Douglas Wright Career Development Award from NHMRC. M.S.P. was supported by an Australian Postgraduate Award. J.M.B. is supported by an International Research Scientist Award from Fogarty International Center, US National Institutes of Health.

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Correspondence to Alex Loukas.

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Supplementary information

Supplementary Table 1

Identification of cohorts of Chronically Infected (CI) and Putatively Resistant (PR) individuals in the S. mansoni endemic area of Siquiera (n = 162). (PDF 59 kb)

Supplementary Table 2

Inclusion and exclusion rules for the assembly and maintenance of resistant cohorts. (PDF 69 kb)

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Tran, M., Pearson, M., Bethony, J. et al. Tetraspanins on the surface of Schistosoma mansoni are protective antigens against schistosomiasis. Nat Med 12, 835–840 (2006).

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