Deciphering the host-pathogen interactions contributing to the severe malaria pathogenesis: Impact of self-medication and parasite genetics (OPTIMA)

One-to three percent of uncomplicated malaria cases progress to the severe stage of the disease, including severe malaria anemia (SMA) and cerebral malaria (CM). Even when treated, cerebral malaria is fatal in 15-20% of CM cases. The factors determining the progression of the malaria pathogenesis are not well understood. The host-pathogen interactions modulate the clinical expression of malaria, from asymptomatic to the SMA or CM forms. The cytoadherence of infected red blood cell (RBC) to endothelial receptors in the host is the main hallmark of the malaria pathogenesis. It is mainly mediated by a P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, encoded by a multigene family of 60 var genes. During the maturation of P. falciparum, the expression of cytoadhesion molecules trigger the cytoadherence and sequestration of infected RBC, initiating the cascade pathogenesis mechanism, including host & parasite molecules interactions, hemolysis & anemia and inflammasome pathway activation. However, pre-existing pathologies, inappropriate treatment inducing delayed parasite clearance may also be involved in anemia (hemolysis and impaired RBC production) and increase pathogenesis mechanisms. Expression of a specific parasite variants: selected or induced should also be taken in account as key factors in the progression of the disease. The hypothesis is that upon infection, if host fails to control the parasite, inappropriate treatment, inappropriate/ineffective host response and or expression of specific proteins from selected variants will contribute to the dynamics of malaria severity. This would decipher the mechanism of anemia and increasing cytoadherence according to the clinical form with or without self-antimalarial pretreatment. Using an in vitro model, the project will determine whether (as suggested by our preliminary data) isolates from severe forms preferentially infect immature erythrocytes and increase cytoadherence and sequestration. In parallel, their pre- and post-invasion transcriptomic profile associated with clinical form and anemia will also be analyzed. Using an ex-vivo splenomimetic and an in vitro model, cellular and molecular property of infected or uninfected circulating RBC will be explored during severe malaria correlated with host immune response and RBC clearance mechanisms. Using new methods developed by our consortium, this study will detect and determine the impact of self an inappropriate antimalarial drug in severe malaria progression. Finally, a comparison of CM, SMA, UM, SA and healthy controls will be performed in an integrated clinical, biological, proteotranscriptomic and metabolomic analysis to better understand the dynamics of severe malaria pathogenesis and expect to validate key factors and identify potential biomarkers. The final products of the OPTIMA project will feed, the pipeline of new diagnosis, therapeutic and preventive strategies (severity biomarker) that would improve the management of severe malaria pathogenesis.

Project details

Basic Science

Sep 2023 — Sep 2027

$866,271

France