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. 1996 Apr 16;93(8):3503–3508. doi: 10.1073/pnas.93.8.3503

Variant antigens and endothelial receptor adhesion in Plasmodium falciparum.

J P Gardner 1, R A Pinches 1, D J Roberts 1, C I Newbold 1
PMCID: PMC39639  PMID: 8622966

Abstract

Parasite-derived proteins expressed on the surface of erythrocytes infected with Plasmodium falciparum are important virulence factors, since they mediate binding of infected cells to diverse receptors on vascular endothelium and are targets of a protective immune response. They are difficult to study because they undergo rapid clonal antigenic variation in vitro, which precludes the derivation of phenotypically homogeneous cultures. Here we have utilized sequence-specific proteases to dissect the role of defined antigenic variants in binding to particular receptors. By selection of protease-resistant subpopulations of parasites on defined receptors we (i) confirm the high rate of antigenic variation in vitro; (ii) demonstrate that a single infected erythrocyte can bind to intercellular adhesion molecule 1, CD36, and thrombospondin; (iii) show that binding to intercellular adhesion molecule 1 and CD36 are functions of the variant antigen; and (iv) suggest that binding to thrombospondin may be mediated by other components of the infected erythrocyte surface.

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Selected References

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

  1. Asch A. S., Barnwell J., Silverstein R. L., Nachman R. L. Isolation of the thrombospondin membrane receptor. J Clin Invest. 1987 Apr;79(4):1054–1061. doi: 10.1172/JCI112918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barnwell J. W., Asch A. S., Nachman R. L., Yamaya M., Aikawa M., Ingravallo P. A human 88-kD membrane glycoprotein (CD36) functions in vitro as a receptor for a cytoadherence ligand on Plasmodium falciparum-infected erythrocytes. J Clin Invest. 1989 Sep;84(3):765–772. doi: 10.1172/JCI114234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baruch D. I., Pasloske B. L., Singh H. B., Bi X., Ma X. C., Feldman M., Taraschi T. F., Howard R. J. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell. 1995 Jul 14;82(1):77–87. doi: 10.1016/0092-8674(95)90054-3. [DOI] [PubMed] [Google Scholar]
  4. Berendt A. R., Simmons D. L., Tansey J., Newbold C. I., Marsh K. Intercellular adhesion molecule-1 is an endothelial cell adhesion receptor for Plasmodium falciparum. Nature. 1989 Sep 7;341(6237):57–59. doi: 10.1038/341057a0. [DOI] [PubMed] [Google Scholar]
  5. Biggs B. A., Anders R. F., Dillon H. E., Davern K. M., Martin M., Petersen C., Brown G. V. Adherence of infected erythrocytes to venular endothelium selects for antigenic variants of Plasmodium falciparum. J Immunol. 1992 Sep 15;149(6):2047–2054. [PubMed] [Google Scholar]
  6. Biggs B. A., Goozé L., Wycherley K., Wollish W., Southwell B., Leech J. H., Brown G. V. Antigenic variation in Plasmodium falciparum. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9171–9174. doi: 10.1073/pnas.88.20.9171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brannan L. R., Turner C. M., Phillips R. S. Malaria parasites undergo antigenic variation at high rates in vivo. Proc Biol Sci. 1994 Apr 22;256(1345):71–75. doi: 10.1098/rspb.1994.0051. [DOI] [PubMed] [Google Scholar]
  8. Brittain H. A., Eckman J. R., Swerlick R. A., Howard R. J., Wick T. M. Thrombospondin from activated platelets promotes sickle erythrocyte adherence to human microvascular endothelium under physiologic flow: a potential role for platelet activation in sickle cell vaso-occlusion. Blood. 1993 Apr 15;81(8):2137–2143. [PubMed] [Google Scholar]
  9. Chaiyaroj S. C., Coppel R. L., Magowan C., Brown G. V. A Plasmodium falciparum isolate with a chromosome 9 deletion expresses a trypsin-resistant cytoadherence molecule. Mol Biochem Parasitol. 1994 Sep;67(1):21–30. doi: 10.1016/0166-6851(94)90092-2. [DOI] [PubMed] [Google Scholar]
  10. Chaiyaroj S. C., Coppel R. L., Novakovic S., Brown G. V. Multiple ligands for cytoadherence can be present simultaneously on the surface of Plasmodium falciparum-infected erythrocytes. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10805–10808. doi: 10.1073/pnas.91.23.10805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Crandall I., Collins W. E., Gysin J., Sherman I. W. Synthetic peptides based on motifs present in human band 3 protein inhibit cytoadherence/sequestration of the malaria parasite Plasmodium falciparum. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4703–4707. doi: 10.1073/pnas.90.10.4703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Crandall I., Land K. M., Sherman I. W. Plasmodium falciparum: pfalhesin and CD36 form an adhesin/receptor pair that is responsible for the pH-dependent portion of cytoadherence/sequestration. Exp Parasitol. 1994 Mar;78(2):203–209. doi: 10.1006/expr.1994.1020. [DOI] [PubMed] [Google Scholar]
  13. Day K. P., Karamalis F., Thompson J., Barnes D. A., Peterson C., Brown H., Brown G. V., Kemp D. J. Genes necessary for expression of a virulence determinant and for transmission of Plasmodium falciparum are located on a 0.3-megabase region of chromosome 9. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8292–8296. doi: 10.1073/pnas.90.17.8292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gilks C. F., Walliker D., Newbold C. I. Relationships between sequestration, antigenic variation and chronic parasitism in Plasmodium chabaudi chabaudi--a rodent malaria model. Parasite Immunol. 1990 Jan;12(1):45–64. doi: 10.1111/j.1365-3024.1990.tb00935.x. [DOI] [PubMed] [Google Scholar]
  15. Hasler T., Handunnetti S. M., Aguiar J. C., van Schravendijk M. R., Greenwood B. M., Lallinger G., Cegielski P., Howard R. J. In vitro rosetting, cytoadherence, and microagglutination properties of Plasmodium falciparum-infected erythrocytes from Gambian and Tanzanian patients. Blood. 1990 Nov 1;76(9):1845–1852. [PubMed] [Google Scholar]
  16. Howard R. J., Gilladoga A. D. Molecular studies related to the pathogenesis of cerebral malaria. Blood. 1989 Dec;74(8):2603–2618. [PubMed] [Google Scholar]
  17. Howard R. J. Malarial proteins at the membrane of Plasmodium falciparum-infected erythrocytes and their involvement in cytoadherence to endothelial cells. Prog Allergy. 1988;41:98–147. doi: 10.1159/000415221. [DOI] [PubMed] [Google Scholar]
  18. Leech J. H., Barnwell J. W., Miller L. H., Howard R. J. Identification of a strain-specific malarial antigen exposed on the surface of Plasmodium falciparum-infected erythrocytes. J Exp Med. 1984 Jun 1;159(6):1567–1575. doi: 10.1084/jem.159.6.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. MacPherson G. G., Warrell M. J., White N. J., Looareesuwan S., Warrell D. A. Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol. 1985 Jun;119(3):385–401. [PMC free article] [PubMed] [Google Scholar]
  20. Magowan C., Wollish W., Anderson L., Leech J. Cytoadherence by Plasmodium falciparum-infected erythrocytes is correlated with the expression of a family of variable proteins on infected erythrocytes. J Exp Med. 1988 Oct 1;168(4):1307–1320. doi: 10.1084/jem.168.4.1307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Marsh K., Howard R. J. Antigens induced on erythrocytes by P. falciparum: expression of diverse and conserved determinants. Science. 1986 Jan 10;231(4734):150–153. doi: 10.1126/science.2417315. [DOI] [PubMed] [Google Scholar]
  22. Marsh K., Otoo L., Hayes R. J., Carson D. C., Greenwood B. M. Antibodies to blood stage antigens of Plasmodium falciparum in rural Gambians and their relation to protection against infection. Trans R Soc Trop Med Hyg. 1989 May-Jun;83(3):293–303. doi: 10.1016/0035-9203(89)90478-1. [DOI] [PubMed] [Google Scholar]
  23. Newbold C. I., Pinches R., Roberts D. J., Marsh K. Plasmodium falciparum: the human agglutinating antibody response to the infected red cell surface is predominantly variant specific. Exp Parasitol. 1992 Nov;75(3):281–292. doi: 10.1016/0014-4894(92)90213-t. [DOI] [PubMed] [Google Scholar]
  24. Ockenhouse C. F., Ho M., Tandon N. N., Van Seventer G. A., Shaw S., White N. J., Jamieson G. A., Chulay J. D., Webster H. K. Molecular basis of sequestration in severe and uncomplicated Plasmodium falciparum malaria: differential adhesion of infected erythrocytes to CD36 and ICAM-1. J Infect Dis. 1991 Jul;164(1):163–169. doi: 10.1093/infdis/164.1.163. [DOI] [PubMed] [Google Scholar]
  25. Ockenhouse C. F., Tegoshi T., Maeno Y., Benjamin C., Ho M., Kan K. E., Thway Y., Win K., Aikawa M., Lobb R. R. Human vascular endothelial cell adhesion receptors for Plasmodium falciparum-infected erythrocytes: roles for endothelial leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1. J Exp Med. 1992 Oct 1;176(4):1183–1189. doi: 10.1084/jem.176.4.1183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pongponratn E., Riganti M., Punpoowong B., Aikawa M. Microvascular sequestration of parasitized erythrocytes in human falciparum malaria: a pathological study. Am J Trop Med Hyg. 1991 Feb;44(2):168–175. doi: 10.4269/ajtmh.1991.44.168. [DOI] [PubMed] [Google Scholar]
  27. Roberts D. D., Sherwood J. A., Spitalnik S. L., Panton L. J., Howard R. J., Dixit V. M., Frazier W. A., Miller L. H., Ginsburg V. Thrombospondin binds falciparum malaria parasitized erythrocytes and may mediate cytoadherence. Nature. 1985 Nov 7;318(6041):64–66. doi: 10.1038/318064a0. [DOI] [PubMed] [Google Scholar]
  28. Roberts D. J., Biggs B. A., Brown G., Newbold C. I. Protection, pathogenesis and phenotypic plasticity in Plasmodium falciparum malaria. Parasitol Today. 1993 Aug;9(8):281–286. doi: 10.1016/0169-4758(93)90121-u. [DOI] [PubMed] [Google Scholar]
  29. Roberts D. J., Craig A. G., Berendt A. R., Pinches R., Nash G., Marsh K., Newbold C. I. Rapid switching to multiple antigenic and adhesive phenotypes in malaria. Nature. 1992 Jun 25;357(6380):689–692. doi: 10.1038/357689a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rogerson S. J., Chaiyaroj S. C., Ng K., Reeder J. C., Brown G. V. Chondroitin sulfate A is a cell surface receptor for Plasmodium falciparum-infected erythrocytes. J Exp Med. 1995 Jul 1;182(1):15–20. doi: 10.1084/jem.182.1.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Smith J. D., Chitnis C. E., Craig A. G., Roberts D. J., Hudson-Taylor D. E., Peterson D. S., Pinches R., Newbold C. I., Miller L. H. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell. 1995 Jul 14;82(1):101–110. doi: 10.1016/0092-8674(95)90056-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Udeinya I. J., Miller L. H., McGregor I. A., Jensen J. B. Plasmodium falciparum strain-specific antibody blocks binding of infected erythrocytes to amelanotic melanoma cells. Nature. 1983 Jun 2;303(5916):429–431. doi: 10.1038/303429a0. [DOI] [PubMed] [Google Scholar]

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