Editing CD36 (section)

=== Malaria ===

Infections with the human malaria parasite ''[[Plasmodium falciparum]]'' are characterized by sequestration of erythrocytes infected with mature forms of the parasite and CD36 has been shown to be a major sequestration receptor on [[microvascular]] endothelial cells. Parasitised erythrocytes adhere to endothelium at the [[trophozoite]]/[[wiktionary:schizont|schizonts]] stage simultaneous with the appearance of the ''var'' gene product (erythrocyte membrane protein 1) on the erythrocyte surface. The appearance of [[Plasmodium falciparum erythrocyte membrane protein 1|''Plasmodium falciparum'' erythrocyte membrane protein 1]] (PfEMP1) on the erythrocyte surface is a [[temperature]] dependent phenomenon which is due to increased protein trafficking to the erythrocyte surface at the raised temperature. PfEMP1 can bind other endothelial receptors - [[thrombospondin]] (TSP) and intercellular adhesion molecule 1 ([[ICAM-1]]) – in addition to CD36 - and genes other than PfEMP1 also bind to CD36: [[cytoadherence linked protein]] (clag) and [[sequestrin]]. The PfEMP1 binding site on CD36 is known to be located on exon 5.

CD36 on the surface of the platelets has been shown to be involved in adherence but direct adherence to the endothelium by the infected erythrocytes also occurs. Autoaggregation of infected erythrocytes by platelets has been shown to correlate with severe malaria and cerebral malaria in particular and antiplatelet antibodies may offer some protection.

Several lines of evidence suggest that mutations in CD36 are protective against malaria: mutations in the [[promoter (biology)|promoters]] and within introns and in exon 5 reduce the risk of severe malaria. Gene diversity studies suggest there has been positive selection on this gene presumably due to malarial selection pressure. Dissenting reports are also known 
suggesting that CD36 is not the sole determinant of severe malaria. In addition a role for CD36 has been found in the clearance of [[gametocyte]]s (stages I and II).

CD36 has been shown to have a role in the innate immune response to malaria in mouse models.<ref name="pmid17339496">{{cite journal | vauthors = Patel SN, Lu Z, Ayi K, Serghides L, Gowda DC, Kain KC | title = Disruption of CD36 impairs cytokine response to Plasmodium falciparum glycosylphosphatidylinositol and confers susceptibility to severe and fatal malaria in vivo | journal = Journal of Immunology | volume = 178 | issue = 6 | pages = 3954–61 | date = March 2007 | pmid = 17339496 | doi = 10.4049/jimmunol.178.6.3954 | doi-access = free }}</ref> Compared with wild type mice CD36 (-/-) mice the cytokine induction response and parasite clearance were impaired. Earlier peak parasitemias, higher parasite densities and higher mortality were noted. It is thought that CD36 is involved in the ''[[Plasmodium falciparum]]'' [[glycophosphatidylinositol]] (PfGPI) induced [[MAPK]] activation and proinflammatory cytokine secretion. When macrophages were exposed to PfGPI the proteins ERK1/2, JNK, p38, and c-Jun became phosphorylated. All these proteins are involved as secondary messengers in the immune response. These responses were blunted in the CD36 (-/-) mice. Also in the CD36 (-/-) macrophages secreted significantly less TNF-alpha on exposure to PfGPI. Work is ongoing to determine how these exactly how these responses provide protection against malaria.