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Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2018.00050

Gametocytes of the malaria parasite Plasmodium falciparum interact with and stimulate bone marrow mesenchymal cells to secrete angiogenetic factors

 Valeria Messina1, Mauro Valtieri1,  Mercedes Rubio2,  Mario Falchi1, Francesca Mancini3, Alfredo Mayor2,  Pietro Alano1 and  Francesco Silvestrini1*
  • 1Istituto Superiore di Sanità, Italy
  • 2Global Health Institute Barcelona (ISGlobal), Spain
  • 3Policlinico Umberto I, Italy

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 13 cytokines and growth factors, 11 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.

Keywords: Malaria, Falciparum, gametocytes, Bone Marrow, Host-Parasite Interactions, Angiogenesis

Received: 18 Sep 2017; Accepted: 09 Feb 2018.

Edited by:

Chang H. Kim, Purdue University, United States

Reviewed by:

Kai Matuschewski, Humboldt-Universität zu Berlin, Germany
Ashley Vaughan, Center for Infectious Disease Research, United States
Matthias Marti, Harvard School of Public Health, United States  

Copyright: © 2018 Messina, Valtieri, Rubio, Falchi, Mancini, Mayor, Alano and Silvestrini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Francesco Silvestrini, Istituto Superiore di Sanità, Rome, Italy,