Abstract
The protozoan parasite Plasmodium falciparum, responsible for the most severe form of malaria, is able to sequester from peripheral circulation during infection. The asexual stage parasites sequester by binding to endothelial cell receptors in the microvasculature of various organs. P. falciparum gametocytes, the developmental stages responsible for parasite transmission from humans to Anopheles mosquitoes, also spend the almost ten days necessary for their maturation sequestered away from the peripheral circulation before they are released in blood mainstream. In contrast to those of asexual parasites, the mechanisms and cellular interactions responsible for immature gametocyte sequestration are largely unexplored, and controversial evidence has been produced so far on this matter. Here we present a systematic comparison of cell binding properties of asexual stages and immature and mature gametocytes from the reference P. falciparum clone 3D7 and from a patient parasite isolate on a panel of human endothelial cells from different tissues. This analysis includes assays on human bone marrow derived endothelial cell lines (HBMEC), as this tissue has been proposed as a major site of gametocyte maturation. Our results clearly demonstrate that cell adhesion of asexual stage parasites is consistently more efficient than that, virtually undetectable of immature gametocytes, irrespectively of the endothelial cell lines used and of parasite genotypes. Importantly, immature gametocytes of both lines tested here do not show a higher binding efficiency compared to asexual stages on bone marrow derived endothelial cells, unlike previously reported in the only study on this issue. This indicates that gametocyte-host interactions in this tissue are unlikely to be mediated by the same adhesion processes to specific endothelial receptors as seen with asexual forms.
Highlights
Plasmodium falciparum-infected erythrocytes are characterized by their ability to adhere to the endothelial cells lining the microvasculature of various organs
Two preliminary sets of experiments were performed with the human umbilical vein endothelial cells (HUVEC), human dermal microvascular endothelial cells (HDMEC) and human bone marrow derived endothelial cell lines (HBMEC)-60 endothelial cell lines
This experiment (Figure S1) confirmed that the host ligands were induced by the cytokine, and showed that HUVEC and HBMEC are essentially ICAM-1-positive/CD36-negative, while HDMEC are ICAM-1/CD36-double positive [9,16], providing cues to the functional role of such receptors in this comparative analysis
Summary
Plasmodium falciparum-infected erythrocytes are characterized by their ability to adhere to the endothelial cells lining the microvasculature of various organs. Adhesion of the asexual (trophozoite/schizont) stage-infected erythrocytes and their sequestration away from the peripheral circulation is implicated in malaria pathogenesis. Members of the P. falciparum Erythocyte Membrane Protein-1 (PfEMP-1) family of variable surfaceexpressed parasite antigens have been shown as parasite ligands mediating adhesion of asexual-stage-infected erythrocytes. In P. falciparum asexual stages are able to sequester in internal organs. A portion of parasites in the bloodstream does not progress into the asexual cycle but differentiate into gametocytes, the parasite stages able to mature into gametes when engorged in the blood meal of a biting Anopheles mosquito, and responsible of Plasmodium transmission from humans to the insect vector. Immature gametocytes (stages I to IV), like asexual stages, have instead the ability to sequester in poorly defined body sites, from which they are released only when they reach maturity
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