Sequestrin, a CD36 recognition protein on Plasmodium falciparum malaria-infected erythrocytes identified by anti-idiotype antibodies.

Abstract

The CD36 molecule expressed by human endothelial cells is a receptor for the adhesion of erythrocytes infected with the human malaria parasite Plasmodium falkiparum. A CD36-speciflic monoclonal antibody, OKM8, inhibits the adhesion of malaria-infected erythrocytes (IRBC) to purified CD36 and cells expressing CD36. Monospecific polyconal anti-idiotype (anti-Id) antibodies, raised against monoclonal antibody OKM8, expressed determinants molecularly mimicking the CD36 binding domain for the adhesion of IRBC. Purified rabbit anti-Id antibodies reacted with the surface of IRBC by immunofluorescence, directly supported the adhesion of wild-type P. falciparum malaria isolates, and inhibited IRBC cytoadherence to melanoma cells. An -270-kDa protein was immunoprecipitated by the anti-Id antibodies from surfacelabeled and metabolically labeled IRBC and was competitively inhibited by soluble CD36. These results support the hypothesis that CD36 is a receptor and the =270-kDa protein, sequestrin, is a complementary ligand involved in the adhesion of IRBC to host-cell endothelium. Sequestrin is a candidate malaria vaccine antigen, and anti-Id antibodies that recognize this molecule may be useful for passive immunotherapy of cerebral and severe P. fakiparum malaria.Erythrocytes infected with the human malaria parasite Plasmodiumfalciparum adhere to postcapillary venular endothehum of specific organs and tissues, and the sequestration of infected erythrocytes (IRBC) contributes to the morbidity and mortality of severe and cerebral malaria (1). Cytoadherence of IRBC has been studied in vitro and involves specific receptor/ligand-mediated interactions between one or more IRBC binding ligands and host endothelial receptors CD36 (2-4), thrombospondin (5), and intercellular adhesion molecule 1 (ICAM-1) (6). CD36 appears to be a major surface receptor for the adhesion of IRBC. Purified CD36 binds culture-adapted (3) and naturally acquired wild-type P. falciparum-IRBC (unpublished data). Soluble CD36 inhibits IRBC binding to endothelial cells and melanoma cells bearing surface CD36.The distribution of CD36 in vivo correlates with sequestration of IRBC, and CD36 is expressed by the capillary endothelium of postmortem brain tissue from patients with cerebral malaria (4). The cytoadherence of IRBC to purified CD36 or cells expressing CD36 is inhibited by monoclonal antibodies (mAbs) OKM8 and OKM5 (2, 7). Based on the above observations, we sought to develop an immunologic monospecific probe to define the malaria-IRBC surface molecule mediating cytoadherence. Such an antibody would focus on the ligand specificity of the CD36 receptor as expressed by an anti-idiotype (anti-Id).Anti-Id antibodies raised against the antigen binding sites of antibodies specific for receptors have been used as cellsurface probes to define the molecular interactions between ligands and receptors (8). Some anti-Id antibodies contain the internal image of the receptor (Ab2) and may recognize a complementary receptor-binding site. In this report we descri...

Cytoadherence characteristics of Plasmodium falciparum-infected erythrocytes from Malawian children with severe and uncomplicated malaria.

“…Such a vaccine, if successful, could select positively for more pathogenic variants that use alternative sequestration receptors expressed on cerebral endothelium. Further evaluation of vaccine candidates derived from sequestrin 31 or P. falciparum erythrocyte membrane protein 1 32 will need to take this possibility into account.…”

Host—parasite interaction and morbidity in malaria endemic areas

“…Several putative endothelial receptors have been identi¢ed, including thrombospondin (Roberts et al 1985), CD36 (Barnwell et al 1989), ICAM 1 (Berendt et al 1989),VCAM and Eselectin (Ockenhouse et al 1992). On the infected red cell side of the interactionthere is evidence thatboth modi¢ed host band three (Sherman et al 1992) and a conserved parasite molecule, sequestrin (Ockenhouse et al 1991), may play a role in binding to CD36. However, increasingly strong evidence suggests that most cytoadherence interactions are mediated by a family of hypervariable parasite proteins, Pfemp1, inserted into the host cell membrane (Magowan et al 1988;Baruch et al 1995;Gardener et al1996).…”

Low antibody responses to variant surface antigens of Plasmodium falciparum are associated with severe malaria and increased susceptibility to malaria attacks in Gabonese children.

“…8 PfEMP-1 proteins are encoded by members of a multigene family, designated var, and are thought to be involved in rosette formation and adhesion to endothelial cells lining postcapillary venules via interactions with a number of host receptors, including the leukocyte differentiation antigens CD36 and CD54, as well as other host adhesive ligands. [9][10][11][12][13][14][15][16][17] A second family of variable parasite antigens, the rifins, has recently been described, and they also may contribute to the constellation of antibody-inducing VSA expressed on IE. 18,19 Naturally acquired antibodies agglutinate parasite-infected erythrocytes in a variant-specific manner, and switches in agglutinating phenotype correlate with switches in cytoadherent phenotype and var gene expression.…”