Gametocytes of the Malaria Parasite Plasmodium falciparum Interact With and Stimulate Bone Marrow Mesenchymal Cells to Secrete Angiogenetic Factors

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.

Plasmodium asexual growth and sexual development in the haematopoietic niche of the host

“…Given the shared binding phenotype to human bone marrow MSCs, it is most likely that such shared antigens are also involved in iRBC interactions in the extravascular bone marrow niche. Interestingly, the presence of parasite antigens on the gametocyte iRBC surface is limited to stages I and II, after which the antigens are gradually removed by as yet unknown processes 77 , coinciding with the observed loss of binding 74 . Invasion assays with P. falciparum and P. berghei have demonstrated that the earliest RBC precursor stage that can be invaded and support parasite growth is the orthochromatic erythroblast 51,60,80 , in the final 48-72 h of erythropoiesis.…”

“…Interestingly, a recent study reported the binding of both asexual stages and immature P. falciparum gametocytes to human bone marrow mesenchymal stem cells (MSCs) in a 3D culture system. This binding was trypsin-sensitive, but independent of PfEMP1 and ICAM1, yet the receptor for the interaction could not be identified 74 . In a separate study, no binding to RBC precursor cells was observed 75 .…”

Intravital microscopy: Imaging host–parasite interactions in lymphoid organs

“…Only in the last decade has Plasmodium transmission biology research re‐gained great momentum, leading to a large number of questions regarding Plasmodium interactions in the bone marrow, including mechanisms of extravasation, development and egress (Aguilar et al, ; Aingaran et al, ; Farfour et al, ; Joice et al, ; Lavazec, ; Lavazec et al, ; Lavazec & Alano, ; Messina et al, ; Naissant et al, ; Neveu et al, ; Ramdani et al, ; Rogers et al, ). Beyond P. falciparum , the bone marrow has been shown to be an important niche for P. vivax development, including gametocyte maturation and asexual development responsible for chronicity (Baro et al, ; Markus, ; Mayor & Alano, ; Obaldia et al, ).…”

“…However, histology techniques combined with human and animal autopsies have shown that the bone marrow can influence pathology related to parasitic infections and in some cases, is even a key niche for parasite development. Direct and indirect bone marrow involvement in pathology has been suggested for parasites including Plasmodium spp., (Alano, 2017;Baro et al, 2017;De Niz et al, 2018;Duffier et al, 2016;Farfour et al 2012;Joice et al, 2014;Lee et al, 2017;Lee et al, 2018;Mayor & Alano, 2015;Messina et al, 2018;Neveu et al, 2018;Rogers et al, 2000;Smalley et al 1981;Waseem et al, 2016;Wickramasinghe et al, 1987), Toxoplasma gondii (Brouland et al, 1996), Leishmania spp., (Ali & Hussain, 2014;Hellal & Kundu, 2013;Kumar et al, 2007), Schistosoma spp., (Azevedo et al, 2015;Jones & Leday, 2014;Kamal et al 1989) and Trypanosoma spp. (Baena Terán et al, 2012;Bockstal, Guirnalda, et al, 2011;Bockstal, Geurts, & Magez, 2011;Carbajosa et al, 2017;De Diego et al 1998;Felizardo et al, 2018;Habila et al, 2014;Mabbott & Sternberg, 1995;Müller et al, 2018;Obishakin et al 2014;Souza et al, 2014;Stijlemans et al, 2016).…”

“…Only in the last decade has Plasmodium transmission biology research re-gained great momentum, leading to a large number of questions regarding Plasmodium interactions in the bone marrow, including mechanisms of extravasation, development and egress (Aguilar et al, 2014;Aingaran et al, 2012;Farfour et al, 2012;Joice et al, 2014;Lavazec, 2017;Lavazec et al, 2013;Lavazec & Alano, 2014;Messina et al, 2018;Naissant et al, 2016;Neveu et al, 2018;Ramdani et al, 2015;Rogers et al, 2000). Beyond P.…”