Malaria is a mosquito-borne infectious disease caused by parasites of the Plasmodium (P) genus and transmitted through the bite of infected female Anopheles mosquitos. P falciparum (Pf), the most frequent and lethal P parasite in humans, differs from the others for the unique feature that both asexual and sexual developmental stages occur largely within organs rather than in blood. While homing and maturation of asexual parasites occurs virtually in all organs, human bone marrow (BM) is emerging as a privileged site for the development of the sexual parasites (gametocytes). This supports a key role of the human BM in the host-parasite interplay and in depth investigations are needed to elucidate mechanisms and cellular players involved in the process. Changes in plasticity of the Pf gametocyte infected erythrocytes (GIEs), now addressable by genetic and chemical approaches, is thought to play a significant role. However, to recapitulate in proper experimental systems the complex architecture and cellular heterogeneity of the human BM microenvironment is still a challenging issue.
Aim of this proposal is to combine a BM Humanized Mouse Model with GIEs. For the development of this system we will use a) human erythrocytes infected with wild type Pf transgenic lines whose gametocytes express fluorescent reporter genes at specific developmental stages and b) hybrid bone/BM organoids generated from human osteoprogenitor cells grown in "pellet" culture and then transplanted at heterotopic sites into immunodeficient mice. We also plan to test Pf lines mutated for genes involved in the conversion from rigid immature to more deformable mature GIE and/or chemical compounds able to interfere with this process. Through this project we expect to characterize the role of the human BM microenvironment in the homing and maturation of Pf-GIEs and to provide a model to study the mechanisms involved in the transmission of the Pf from humans to the mosquito vectors.
