Parasite-host interaction in the bone marrow: key role in the pathogenesis of Malaria

Studies on the biology and immunopathogenesis of Plasmodium vivax have been neglected due to a mistaken impression that the disease is benign. The detection of all forms of the parasite in peripheral blood suggests the absence of significant levels of tissue sequestration, which could support the absence of disease severity. However, recent evidence has changed this paradigm. First, clinical complications from vivax malaria have been reported. Second, it has been shown that the mature asexual forms of the parasite are able to adhere to endothelial cells and these forms are less abundant in the peripheral blood of patients with vivax malaria, when compared to the young forms. Third, estimation of parasite biomass based on circulating biomarkers indicates that there are parasite reservoirs in the parenchyma of different organs, particularly in patients with clinical complications. In support of these observations, a quantitative depletion of transcripts of mature asexual stages and immature gametocytes has been shown in the blood of patients with vivax malaria, and enrichment of these stages in the sinusoids and bone marrow parenchyma of experimentally infected non-human primates. These observations were confirmed in a case study in Brazil with bone marrow aspirate and blood samples from a patient infected with P. vivax. Furthermore, a similar phenotype was observed in patients infected with P. falciparum and in a murine model of infection. In these studies, haematological changes including severe anemia, dyserythropoiesis and vascular leakage were observed. In this context, it has been shown that there is a crosstalk between infected erythrocytes and resident cells of the bone marrow. Taken together, these observations reveal the bone marrow as a fundamental compartment for the growth and transmission of the parasite, in particular for P. vivax, due to its preference for infection of young erythroid cells residing in the bone marrow. However, the biological relevance of parasite-host interactions established in bone marrow niches is unclear, which represents a key gap in the understanding of malaria pathogenesis. In the bone marrow parenchyma, specialized microenvironments called niches (vascular and endosteal) regulate the maintenance and function of hematopoietic stem cells (HSCs) through an active and complex set of molecules with different cellular functions. In particular, stromal cells and sinusoid endothelial cells play important roles in the growth and maintenance of bone marrow cells. Therefore, the active presence and development of asexual and sexual forms of Plasmodium in the bone marrow raise questions regarding cellular and molecular interactions established between infected erythrocytes and hematopoietic niches. In accordance with the main objective of  the project, the study also also measured, in the plasma of healthy subjects and patients with vivax malaria, the concentration of some molecules involved with thrombopoiesis and hematopoiesis. Preliminary data demonstrate that systemic changes occur during P. vivax infection, which may reflect changes in the bone marrow. Therefore, current working hypothesis is based on the fact that the bone marrow, as one of the main reservoirs of the parasite, may contribute to the persistence and pathogenesis of vivax malaria. In this context, this project will contribute to a better understanding of the biology and pathogenesis of P. vivax and to efforts to reduce the severity of this important human disease.

Project details

Basic Science
P. vivax

May 2019 — May 2020

Brazil