Abstract
The gametocytes of Plasmodium falciparum, responsible for the transmission of this malaria parasite from humans to mosquitoes, accumulate and mature preferentially in the human bone marrow. In the 10 day long sexual development of P. falciparum, the immature gametocytes reach and localize in the extravascular compartment of this organ, in contact with several bone marrow stroma cell types, prior to traversing the endothelial lining and re-entering in circulation at maturity. To investigate the host parasite interplay underlying this still obscure process, we developed an in vitro tridimensional co-culture system in a Matrigel scaffold with P. falciparum gametocytes and self-assembling spheroids of human bone marrow mesenchymal cells (hBM-MSCs). Here we show that this co-culture system sustains the full maturation of the gametocytes and that the immature, but not the mature, gametocytes adhere to hBM-MSCs via trypsin-sensitive parasite ligands exposed on the erythrocyte surface. Analysis of a time course of gametocytogenesis in the co-culture system revealed that gametocyte maturation is accompanied by the parasite induced stimulation of hBM-MSCs to secrete a panel of 14 cytokines and growth factors, 13 of which have been described to play a role in angiogenesis. Functional in vitro assays on human bone marrow endothelial cells showed that supernatants from the gametocyte mesenchymal cell co-culture system enhance ability of endothelial cells to form vascular tubes. These results altogether suggest that the interplay between immature gametocytes and hBM-MSCs may induce functional and structural alterations in the endothelial lining of the human bone marrow hosting the P. falciparum transmission stages.
Highlights
The parasite Plasmodium falciparum causes the most severe form of malaria with around 438,000 deaths annually, mostly young children and pregnant women in sub-Saharan Africa (WHO, 2016)
Evidence supporting the existence of such an interplay recently came from the report that vesicles secreted by asexual parasite-infected erythrocytes are able to increase permeability of the endothelial lining (Mantel et al, 2016). To experimentally address these questions, we investigated the cellular interactions between human bone marrow endothelial and stromal cells and immature and mature P. falciparum gametocytes in vitro
Apart from one report (Rogers et al, 2000), all subsequent studies failed to show binding of red blood cells infected by immature gametocytes, produced by laboratory strains and by one wild isolate, to human endothelial cell lines derived from bone marrow, and other organs (Rogers et al, 1996; Silvestrini et al, 2012; Tibúrcio et al, 2013)
Summary
The parasite Plasmodium falciparum causes the most severe form of malaria with around 438,000 deaths annually, mostly young children and pregnant women in sub-Saharan Africa (WHO, 2016). The global fight to control and to eventually eradicate malaria requires a multifaceted approach in which interventions that prevent transmission of Plasmodium from the infected individual to the mosquito have been prioritized. To this aim understanding the fundamental mechanisms of gametocyte maturation in the human host is essential to identify mechanisms that can be targeted by novel vaccines and drugs with transmission-blocking activity (Wells et al, 2009; Alonso et al, 2011; Lindblade et al, 2013). P. falciparum has a complex life cycle, in which asexual replication and sexual development take place in red blood cells (RBCs) of the human host and sexual reproduction in the mosquito vector. Gametocytes undergo a development process classically divided into 5 morphological stages (I-V) that lasts about 10 days (Hawking et al, 1971), in which immature stages sequester in internal organs and only the mature stage V are released back into the blood stream where they can be harvested by the mosquito vector with the blood meal
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