Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance

Plasmodim falciparum is the most lethal form of malaria and is increasing b oth in incidence and in its resistance to antimalarial agents. An improved understanding of the mechanisms of malarial clearance may facilitate the de velopment of new therapeutic interventions. We postulated that the scavenge r receptor CD36, an important factor in cytoadherence of Pfalciparum-parasi tized erythrocytes (PEs), might also play a role in monocyte- and macrophag e-mediated malarial clearance. Exposure of nonopsonized PEs to Fe receptor- blocked monocytes resulted in significant PE phagocytosis, accompanied by i ntense clustering of CD36 around the PEs, Phagocytosis was blocked 60% to 7 0% by monocyte pretreatment with monoclonal anti-CD36 antibodies but not by antibodies to alpha (v)beta (3), thrombospondin, intercellular adhesion mo lecule-1, or platelet/endothelial cell adhesion molecule-1. Antibody-induce d CD36 cross-linking did result in the early increase of surface CD11b expr ession, but there was no increase in, or priming for, tumor necrosis factor (TNF)-alpha secretion following either CD36 crosslinking or PE phagocytosi s. CD36 clustering does support intracellular signaling: Antibody-induced c ross-linking initiated intracellular tyrosine phosphorylation as well as ex tracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) phosphorylation. Both broad-spectrum tyrosine kinase inhibit ion (genistein) and selective ERK and p38 MAPK inhibition (PD98059 and SB20 3580, respectively) reduced PE uptake to almost the same extent as CD36 blo ckade. Thus, CD36-dependent binding and signaling appears to be crucial for the nonopsonic clearance of PEs and does not appear to contribute to the i ncrease in TNF-alpha that is prognostic of poor outcome in clinical malaria . (C) 2000 by The American Society of Hematology.