Skip to main content
PMC home page
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1997 Sep 29;352(1359):1317–1325. doi: 10.1098/rstb.1997.0116

Genetic analysis of host-parasite coevolution in human malaria.

A V Hill 1, A Jepson 1, M Plebanski 1, S C Gilbert 1
PMCID: PMC1692024  PMID: 9355123

Abstract

Recent twin studies of clinical malaria and immune responses to malaria antigens have underscored the importance of both major histocompatability complex (MHC) and non-MHC genes in determining variable susceptibility and immune responsiveness. By using a combination of whole genome genetic linkage studies of families and candidate genes analysis, non-MHC genes are being mapped and identified. Human leucocyte antigen (HLA) genotype was found to affect susceptibility to severe malaria in a large study of West African children. T lymphocytes that may mediate such resistance have been identified and their target antigens and epitopes characterized. Some of these epitopes show substantial polymorphism, which appears to result from immune selection pressure. Natural variant epitopes have been found to escape T-cell recognition in cytolytic and other T-cell assays. More recently a novel immune escape mechanism has been described in viral infections, altered peptide ligand antagonism, whereby variants of a T-cell epitope can downregulate or ablate a T cell response to the index peptide. The likely implications of such immune escape mechanisms for the population structure of malaria parasites, for HLA associations with malaria infection and disease, and for the design of new malaria vaccines, are discussed. The evolutionary consequences of such molecular interactions can be assessed by using mathematical models that capture the dynamic of variable host and parasite molecules. Combined genetic, immunological and mathematical analysis of host and parasite variants in natural populations can identify some mechanisms driving host-parasite coevolution.

Full Text

The Full Text of this article is available as a PDF (144.7 KB).

Selected References

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

  1. Aidoo M., Lalvani A., Allsopp C. E., Plebanski M., Meisner S. J., Krausa P., Browning M., Morris-Jones S., Gotch F., Fidock D. A. Identification of conserved antigenic components for a cytotoxic T lymphocyte-inducing vaccine against malaria. Lancet. 1995 Apr 22;345(8956):1003–1007. doi: 10.1016/s0140-6736(95)90754-8. [DOI] [PubMed] [Google Scholar]
  2. Bertoletti A., Sette A., Chisari F. V., Penna A., Levrero M., De Carli M., Fiaccadori F., Ferrari C. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature. 1994 Jun 2;369(6479):407–410. doi: 10.1038/369407a0. [DOI] [PubMed] [Google Scholar]
  3. De Magistris M. T., Alexander J., Coggeshall M., Altman A., Gaeta F. C., Grey H. M., Sette A. Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. Cell. 1992 Feb 21;68(4):625–634. doi: 10.1016/0092-8674(92)90139-4. [DOI] [PubMed] [Google Scholar]
  4. Doolan D. L., Saul A. J., Good M. F. Geographically restricted heterogeneity of the Plasmodium falciparum circumsporozoite protein: relevance for vaccine development. Infect Immun. 1992 Feb;60(2):675–682. doi: 10.1128/iai.60.2.675-682.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Good M. F., Berzofsky J. A., Miller L. H. The T cell response to the malaria circumsporozoite protein: an immunological approach to vaccine development. Annu Rev Immunol. 1988;6:663–688. doi: 10.1146/annurev.iy.06.040188.003311. [DOI] [PubMed] [Google Scholar]
  6. Gupta S., Trenholme K., Anderson R. M., Day K. P. Antigenic diversity and the transmission dynamics of Plasmodium falciparum. Science. 1994 Feb 18;263(5149):961–963. doi: 10.1126/science.8310293. [DOI] [PubMed] [Google Scholar]
  7. Guttinger M., Caspers P., Takacs B., Trzeciak A., Gillessen D., Pink J. R., Sinigaglia F. Human T cells recognize polymorphic and non-polymorphic regions of the Plasmodium falciparum circumsporozoite protein. EMBO J. 1988 Aug;7(8):2555–2558. doi: 10.1002/j.1460-2075.1988.tb03104.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hill A. V., Allsopp C. E., Kwiatkowski D., Anstey N. M., Twumasi P., Rowe P. A., Bennett S., Brewster D., McMichael A. J., Greenwood B. M. Common west African HLA antigens are associated with protection from severe malaria. Nature. 1991 Aug 15;352(6336):595–600. doi: 10.1038/352595a0. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Hill A. V. Genetic susceptibility to malaria and other infectious diseases: from the MHC to the whole genome. Parasitology. 1996;112 (Suppl):S75–S84. doi: 10.1017/s003118200007668x. [DOI] [PubMed] [Google Scholar]
  11. Hill A. V., Yates S. N., Allsopp C. E., Gupta S., Gilbert S. C., Lalvani A., Aidoo M., Davenport M., Plebanski M. Human leukocyte antigens and natural selection by malaria. Philos Trans R Soc Lond B Biol Sci. 1994 Nov 29;346(1317):379–385. doi: 10.1098/rstb.1994.0155. [DOI] [PubMed] [Google Scholar]
  12. Hughes A. L. Positive selection and interallelic recombination at the merozoite surface antigen-1 (MSA-1) locus of Plasmodium falciparum. Mol Biol Evol. 1992 May;9(3):381–393. doi: 10.1093/oxfordjournals.molbev.a040730. [DOI] [PubMed] [Google Scholar]
  13. Jepson A. P., Banya W. A., Sisay-Joof F., Hassan-King M., Bennett S., Whittle H. C. Genetic regulation of fever in Plasmodium falciparum malaria in Gambian twin children. J Infect Dis. 1995 Jul;172(1):316–319. doi: 10.1093/infdis/172.1.316. [DOI] [PubMed] [Google Scholar]
  14. Jepson A., Banya W., Sisay-Joof F., Hassan-King M., Nunes C., Bennett S., Whittle H. Quantification of the relative contribution of major histocompatibility complex (MHC) and non-MHC genes to human immune responses to foreign antigens. Infect Immun. 1997 Mar;65(3):872–876. doi: 10.1128/iai.65.3.872-876.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jepson A., Sisay-Joof F., Banya W., Hassan-King M., Frodsham A., Bennett S., Hill A. V., Whittle H. Genetic linkage of mild malaria to the major histocompatibility complex in Gambian children: study of affected sibling pairs. BMJ. 1997 Jul 12;315(7100):96–97. doi: 10.1136/bmj.315.7100.96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Klenerman P., Rowland-Jones S., McAdam S., Edwards J., Daenke S., Lalloo D., Köppe B., Rosenberg W., Boyd D., Edwards A. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature. 1994 Jun 2;369(6479):403–407. doi: 10.1038/369403a0. [DOI] [PubMed] [Google Scholar]
  17. Lalvani A., Hurt N., Aidoo M., Kibatala P., Tanner M., Hill A. V. Cytotoxic T lymphocytes to Plasmodium falciparum epitopes in an area of intense and perennial transmission in Tanzania. Eur J Immunol. 1996 Apr;26(4):773–779. doi: 10.1002/eji.1830260408. [DOI] [PubMed] [Google Scholar]
  18. Lark K. G., Chase K., Adler F., Mansur L. M., Orf J. H. Interactions between quantitative trait loci in soybean in which trait variation at one locus is conditional upon a specific allele at another. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4656–4660. doi: 10.1073/pnas.92.10.4656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. McGuire W., Hill A. V., Allsopp C. E., Greenwood B. M., Kwiatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature. 1994 Oct 6;371(6497):508–510. doi: 10.1038/371508a0. [DOI] [PubMed] [Google Scholar]
  21. Miyahira Y., Murata K., Rodriguez D., Rodriguez J. R., Esteban M., Rodrigues M. M., Zavala F. Quantification of antigen specific CD8+ T cells using an ELISPOT assay. J Immunol Methods. 1995 Apr 12;181(1):45–54. doi: 10.1016/0022-1759(94)00327-s. [DOI] [PubMed] [Google Scholar]
  22. Nardin E. H., Nussenzweig R. S. T cell responses to pre-erythrocytic stages of malaria: role in protection and vaccine development against pre-erythrocytic stages. Annu Rev Immunol. 1993;11:687–727. doi: 10.1146/annurev.iy.11.040193.003351. [DOI] [PubMed] [Google Scholar]
  23. Plebanski M., Aidoo M., Whittle H. C., Hill A. V. Precursor frequency analysis of cytotoxic T lymphocytes to pre-erythrocytic antigens of Plasmodium falciparum in West Africa. J Immunol. 1997 Mar 15;158(6):2849–2855. [PubMed] [Google Scholar]
  24. Robson K. J., Hall J. R., Davies L. C., Crisanti A., Hill A. V., Wellems T. E. Polymorphism of the TRAP gene of Plasmodium falciparum. Proc Biol Sci. 1990 Dec 22;242(1305):205–216. doi: 10.1098/rspb.1990.0126. [DOI] [PubMed] [Google Scholar]
  25. Rook G. A. The role of vitamin D in tuberculosis. Am Rev Respir Dis. 1988 Oct;138(4):768–770. doi: 10.1164/ajrccm/138.4.768. [DOI] [PubMed] [Google Scholar]
  26. Sette A., Alexander J., Ruppert J., Snoke K., Franco A., Ishioka G., Grey H. M. Antigen analogs/MHC complexes as specific T cell receptor antagonists. Annu Rev Immunol. 1994;12:413–431. doi: 10.1146/annurev.iy.12.040194.002213. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Sjöberg K., Lepers J. P., Raharimalala L., Larsson A., Olerup O., Marbiah N. T., Troye-Blomberg M., Perlmann P. Genetic regulation of human anti-malarial antibodies in twins. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2101–2104. doi: 10.1073/pnas.89.6.2101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sloan-Lancaster J., Allen P. M. Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology. Annu Rev Immunol. 1996;14:1–27. doi: 10.1146/annurev.immunol.14.1.1. [DOI] [PubMed] [Google Scholar]
  30. Stoute J. A., Slaoui M., Heppner D. G., Momin P., Kester K. E., Desmons P., Wellde B. T., Garçon N., Krzych U., Marchand M. A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS,S Malaria Vaccine Evaluation Group. N Engl J Med. 1997 Jan 9;336(2):86–91. doi: 10.1056/NEJM199701093360202. [DOI] [PubMed] [Google Scholar]
  31. Tanabe K., Mackay M., Goman M., Scaife J. G. Allelic dimorphism in a surface antigen gene of the malaria parasite Plasmodium falciparum. J Mol Biol. 1987 May 20;195(2):273–287. doi: 10.1016/0022-2836(87)90649-8. [DOI] [PubMed] [Google Scholar]
  32. Taylor R. R., Egan A., McGuinness D., Jepson A., Adair R., Drakely C., Riley E. Selective recognition of malaria antigens by human serum antibodies is not genetically determined but demonstrates some features of clonal imprinting. Int Immunol. 1996 Jun;8(6):905–915. doi: 10.1093/intimm/8.6.905. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES