CD36-Mediated Nonopsonic Phagocytosis of Erythrocytes Infected with Stage I and IIA Gametocytes of Plasmodium falciparum

Abstract

Gametocytes, the sexual stages of malaria parasites (Plasmodium spp.) that are transmissible to mosquitoes, have been the focus of much recent research as potential targets for novel drug and vaccine therapies. However, little is known about the host clearance of gametocyte-infected erythrocytes (GEs). Using a number of experimental strategies, we found that the scavenger receptor CD36 mediates the uptake of nonopsonized erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum by monocytes and culturederived macrophages (Ms). Light microscopy and immunofluorescence assays revealed that stage I and IIA gametocytes were readily internalized by monocytes and Ms. Pretreating monocytes and Ms with a monoclonal antibody that blocked CD36 resulted in a significant reduction in phagocytosis, as did treating GEs with low concentrations of trypsin to remove P. falciparum erythrocyte membrane protein 1 (PfEMP-1), a parasite ligand for CD36. Pretreating monocytes and Ms with peroxisome proliferator-activated receptor ␥-retinoid X receptor agonists, which specifically upregulate CD36, resulted in a significant increase in the phagocytosis of GEs. Murine CD36 on mouse Ms also mediated the phagocytosis of P. falciparum stage I and IIA gametocytes, as determined by receptor blockade with anti-murine CD36 monoclonal antibodies and the lack of uptake by CD36-null Ms. These results indicate that phagocytosis of stage I and IIA gametocytes by monocytes and Ms appears to be mediated to a large extent by the interaction of PfEMP-1 and CD36, suggesting that CD36 may play a role in innate clearance of these early sexual stages.

Epidemiology and Infectivity of Plasmodium falciparum and Plasmodium vivax Gametocytes in Relation to Malaria Control and Elimination

“…For PfEMP-1, it has been suggested that immunity may regulate the densities of both gametocytes and trophozoites by antibody-dependent cell-mediated cytotoxicity reactions (354) and prevention of sequestration (90). The scavenger receptor CD36 was found to mediate the uptake of erythrocytes infected with early-stage gametocytes (I and IIa) by nonopsonic phagocytosis by monocytes and macrophages (436), as was previously shown in the phagocytosis of trophozoites and schizonts (267). In addition to proteins involved in erythrocyte adhesion, molecules on the surfaces of erythrocytes infected with mature gametocytes may also elicit immune responses and may be involved in the clearance of circulating gametocytes.…”

“…24,2011 P. FALCIPARUM AND P. VIVAX GAMETOCYTES 379 become infectious to mosquitoes (243). Early-stage gametocytes (stages I and IIa) seem to depend on CD36 as the principal host ligand for gametocyte adherence (106,193,436); ICAM-1, CD49c, CD166, and CD164 receptors that are present in human bone marrow epithelial and stromal cell lines have been suggested as host ligands for later gametocyte stages (stages III and IV) (113,390). Parasite ligands that mediate adherence are less well characterized but may include the parasite surface proteins PfEMP-1 (P. falciparum erythrocyte membrane protein 1) (105,193,411), RIFIN (repetitive interspersed family) (17, 505), and STEVOR (subtelomeric variable open reading frame) (273,458).…”

Peroxisome Proliferator-Activated Receptor γ and Retinoid X Receptor Agonists Have Minimal Effects on the Interaction of Endothelial Cells withPlasmodium falciparum-Infected Erythrocytes

“…CD36 is transcriptionally regulated by the nuclear receptor peroxisome proliferator-activated receptor ␥-retinoid X receptor (PPAR␥-RXR) (18). PPAR␥-RXR agonists have been shown to increase CD36-mediated phagocytosis of IEs (12,14,15,17) and to reduce GPI-induced tumor necrosis factor alpha (TNF-␣) production (14,15) and have been proposed as potential therapeutics for malaria. However, before this can be explored it is important to investigate their effects on endothelial cell-parasite interactions.…”

Preliminary Investigations into the Binding Interactions between Plasmodial and Host Proteins using Computational Approaches

“…Plasmodial species are the causative organisms for Malaria which are injected into the host blood stream by Anopheles Mosquitoes during a blood meal [1,2]. Malaria has remained an age-long disease which has defied complete cure as a result of repeated re-infection [3,4].…”