Clearance of Plasmodium falciparum-infected Red Blood Cells by Natural Killer cells and Monocytes

Abstract

Abstract Antibodies naturally acquired during repeated exposure to the parasite Plasmodium falciparum are essential for control of blood-stage malaria. Natural killer (NK) cells are innate immune cells with an important role in containing viral infections and tumor growth, mainly by direct cytotoxicity and inflammatory cytokine production. Recently, the lab reported that primary human NK cells lyse Plasmodium falciparum-infected red blood cells (iRBCs) via antibody dependent cellular cytotoxicity (ADCC) in presence of IgG isolated from adults living in a malaria-endemic region of Mali. Using live imaging, I observed release of parasitophorous vacuoles (PV) from iRBCs after incubation with NK cells in the presence of rabbit anti-RBC Abs. I confirmed the imaging results by flow cytometric analysis. Direct interactions of NK cells with iRBCs was imaged by scanning electron microscopy, which revealed tight immunological synapses and extensive damage to iRBC membranes. This membrane damage results in formation of ghost RBCs and eventually release of PVs. We hypothesized that monocytes clear PVs, which could reduce the inflammatory response. I isolated PVs by mild saponin treatment and mechanical disruption of iRBC membranes. Binding of IgG isolated from plasma of Malian adults to PVs was orders of magnitude higher than binding to iRBCs. Phagocytosis of PVs by primary human monocytes was detected and was enhanced in the presence of Mali IgG. Similar results were obtained using PVs released by NK-dependent lysis of iRBCs in the presence of Mali IgG. These results suggest that NK-mediated ADCC inflicts severe damage to the plasma membrane of iRBCs, leading to release of PVs which bind immune serum IgG and are cleared through phagocytosis by monocytes.