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. 1994 Apr;62(4):1410–1413. doi: 10.1128/iai.62.4.1410-1413.1994

Antigenic diversity in the circumsporozoite protein of Plasmodium falciparum abrogates cytotoxic-T-cell recognition.

V Udhayakumar 1, Y P Shi 1, S Kumar 1, D L Jue 1, R M Wohlhueter 1, A A Lal 1
PMCID: PMC186295  PMID: 7510668

Abstract

Genetic analysis of field isolates of Plasmodium falciparum has shown selective accumulation of point mutations within the immunologically sensitive sites of the circumsporozoite (CS) protein, a vaccine candidate against malaria. This raised concern whether a vaccine containing the sequence of a selected strain of P. falciparum would be able to confer protection against other variant parasites. The answer to this question remained speculative, and in this study, we have formally tested the immunological impact of such natural variations within a known cytotoxic-T-cell (CTL) epitope, which is recognized by both human and murine CTLs. With a murine model, CTLs were generated against the 7G8 strain of P. falciparum. The ability of these CTLs to lyse histocompatible targets that were pulsed with synthetic peptides corresponding to polymorphic sequences of Brazilian, Papua New Guinean, and The Gambian isolates was determined. While these CTLs were able to recognize three of the four variant CS sequences found in Brazil and Papua New Guinea, they failed to recognize four of the five variant CS sequences found in The Gambia. Among the peptides that lost their reactivity to 7G8-specific CTL, all except one had amino acid variation in more than one residue. On the other hand, only one of the four peptides that showed a positive reaction had amino acid substitutions in more than a single residue. Thus, our findings demonstrate that natural amino acid variations in the CS protein abrogate CTL recognition. Therefore, it is important to consider the implications of these results in designing CS protein-based vaccines.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Doolan D. L., Houghten R. A., Good M. F. Location of human cytotoxic T cell epitopes within a polymorphic domain of the Plasmodium falciparum circumsporozoite protein. Int Immunol. 1991 Jun;3(6):511–516. doi: 10.1093/intimm/3.6.511. [DOI] [PubMed] [Google Scholar]
  2. Hill A. V., Elvin J., Willis A. C., Aidoo M., Allsopp C. E., Gotch F. M., Gao X. M., Takiguchi M., Greenwood B. M., Townsend A. R. Molecular analysis of the association of HLA-B53 and resistance to severe malaria. Nature. 1992 Dec 3;360(6403):434–439. doi: 10.1038/360434a0. [DOI] [PubMed] [Google Scholar]
  3. Kumar S., Miller L. H., Quakyi I. A., Keister D. B., Houghten R. A., Maloy W. L., Moss B., Berzofsky J. A., Good M. F. Cytotoxic T cells specific for the circumsporozoite protein of Plasmodium falciparum. Nature. 1988 Jul 21;334(6179):258–260. doi: 10.1038/334258a0. [DOI] [PubMed] [Google Scholar]
  4. Lockyer M. J., Marsh K., Newbold C. I. Wild isolates of Plasmodium falciparum show extensive polymorphism in T cell epitopes of the circumsporozoite protein. Mol Biochem Parasitol. 1989 Dec;37(2):275–280. doi: 10.1016/0166-6851(89)90159-x. [DOI] [PubMed] [Google Scholar]
  5. Malik A., Egan J. E., Houghten R. A., Sadoff J. C., Hoffman S. L. Human cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3300–3304. doi: 10.1073/pnas.88.8.3300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Miller L. H., Howard R. J., Carter R., Good M. F., Nussenzweig V., Nussenzweig R. S. Research toward malaria vaccines. Science. 1986 Dec 12;234(4782):1349–1356. doi: 10.1126/science.2431481. [DOI] [PubMed] [Google Scholar]
  7. Phillips R. E., Rowland-Jones S., Nixon D. F., Gotch F. M., Edwards J. P., Ogunlesi A. O., Elvin J. G., Rothbard J. A., Bangham C. R., Rizza C. R. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature. 1991 Dec 12;354(6353):453–459. doi: 10.1038/354453a0. [DOI] [PubMed] [Google Scholar]
  8. Pircher H., Moskophidis D., Rohrer U., Bürki K., Hengartner H., Zinkernagel R. M. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature. 1990 Aug 16;346(6285):629–633. doi: 10.1038/346629a0. [DOI] [PubMed] [Google Scholar]
  9. Sedegah M., Sim B. K., Mason C., Nutman T., Malik A., Roberts C., Johnson A., Ochola J., Koech D., Were B. Naturally acquired CD8+ cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein. J Immunol. 1992 Aug 1;149(3):966–971. [PubMed] [Google Scholar]
  10. Shi Y. P., Alpers M. P., Povoa M. M., Lal A. A. Diversity in the immunodominant determinants of the circumsporozoite protein of Plasmodium falciparum parasites from malaria-endemic regions of Papua New Guinea and Brazil. Am J Trop Med Hyg. 1992 Dec;47(6):844–851. doi: 10.4269/ajtmh.1992.47.844. [DOI] [PubMed] [Google Scholar]
  11. Townsend A., Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol. 1989;7:601–624. doi: 10.1146/annurev.iy.07.040189.003125. [DOI] [PubMed] [Google Scholar]
  12. Yoshida N., Di Santi S. M., Dutra A. P., Nussenzweig R. S., Nussenzweig V., Enea V. Plasmodium falciparum: restricted polymorphism of T cell epitopes of the circumsporozoite protein in Brazil. Exp Parasitol. 1990 Nov;71(4):386–392. doi: 10.1016/0014-4894(90)90064-j. [DOI] [PubMed] [Google Scholar]
  13. de la Cruz V. F., Lal A. A., McCutchan T. F. Sequence variation in putative functional domains of the circumsporozoite protein of Plasmodium falciparum. Implications for vaccine development. J Biol Chem. 1987 Sep 5;262(25):11935–11939. [PubMed] [Google Scholar]
  14. de la Cruz V. F., Maloy W. L., Miller L. H., Lal A. A., Good M. F., McCutchan T. F. Lack of cross-reactivity between variant T cell determinants from malaria circumsporozoite protein. J Immunol. 1988 Oct 1;141(7):2456–2460. [PubMed] [Google Scholar]
  15. del Portillo H. A., Nussenzweig R. S., Enea V. Circumsporozoite gene of a Plasmodium falciparum strain from Thailand. Mol Biochem Parasitol. 1987 Jul;24(3):289–294. doi: 10.1016/0166-6851(87)90161-7. [DOI] [PubMed] [Google Scholar]

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