Plasmodium falciparum causes significant alterations in erythroid differentiation

Aurélie Dumarchey

19 June 2024

Thesis defence

Pratical info

14h00 - 23h00
Conference room Rosalind Franklin
Research professionnals and doctors
Reduced mobility access

Under the supervision of Frédérique Verdier, team biology of plasmodium transmission


During malarial infection, anemia is common and represents a significant cause of mortality and complications among patients. Infection by the Plasmodium parasite, the causative agent of malaria, induces anemia through hemolysis and splenic retention of infected or uninfected erythrocytes. Furthermore, erythropoiesis abnormalities, such as a reduction in erythroid progenitors and inappropriate reticulocytosis relative to the degree of anemia, have been reported in patients, potentially contributing to malarial anemia. Dysfunction in red blood cell production is mediated by various factors generated by both the host and the parasite, including cytokines and hemozoin released during infection. However, the molecular mechanisms underlying erythropoiesis alterations remain poorly defined. Plasmodium falciparum is sequestered and can develop within erythroblastic islands in the bone marrow, where erythropoiesis takes place. Red blood cells infected by this parasite release extracellular vesicles (iEVs) containing biological materials from both the parasite and the host (proteins, nucleic acids, and lipids), which play roles in various biological functions. iEVs influence host-pathogen interactions, modulating the immune response, vascular endothelium integrity, and facilitating parasitic invasion (cytoskeletal network remodelling). Thus, we hypothesize that the parasite alters erythropoiesis and contributes to malarial anemia through iEVs. Recent work from our team has demonstrated that the infection of erythroblasts by the parasite and incubation of orthochromatic erythroblasts with iEVs lead to a delay of enucleation, further supporting our hypothesis. However, the impact of iEVs on other erythroid stages and the molecular pathways affected by them remain unknown. The aim of this thesis is to characterize the effects of iEVs during erythropoiesis and to identify the molecular pathways involved in the dysregulation of erythropoiesis. To this end, erythroid differentiation was studied at various maturation stages in the presence or absence of iEVs, as well as in the presence of EVs derived from uninfected red blood cells. My research reveals a significant delay in maturation at each stage in the presence of iEVs. Additionally, an increase in apoptosis and a decrease in proliferation in the most immature progenitors and erythroblasts were observed. Furthermore, an accumulation of cells at the G1/S phase was noticed, suggesting a cell cycle arrest. Proteomic analysis of erythroblasts in the presence or absence of iEVs revealed alterations in the expression of several proteins involved in erythropoiesis, apoptosis, or the cell cycle, signifying that multiple mechanisms contribute to the delay. Among these proteins, the expression of GATA1, a key transcription factor, was significantly reduced. The role of GATA1 in the dysregulation of erythropoiesis induced by iEVs was thoroughly examined. This project has provided insight the molecular mechanisms of the deregulation of erythropoiesis by the parasite. The erythropoiesis abnormalities identified in vitro may partly explain the anemia observed in malaria patients and lead to a better long-term disease management.

Keywords : erythropoiesis, erythroblasts, bone marrow, anemia, malaria, parasite, Plasmodium falciparum, extracellular vesicles