Mechanisms of dormancy, activation and sexual conversion in pre-erythrocytic malaria parasites (DEXES)

Malaria remains a devastating public health burden – the estimated death toll in 2020 was over 600,000. Its eradication is a desirable goal; however, the development of novel intervention strategies is hampered by limited current understanding of the biology of Plasmodium, the causative agent of malaria, and of its complex interactions with mammalian and mosquito hosts. In the liver, inside hepatocytes, Plasmodium parasites can either 1) replicate, forming new parasites that will infect erythrocytes and cause disease, or 2) remain dormant, which can lead to chronic, relapsing disease weeks to years after the original infection. New hepatic outcomes were recently discovered using a novel pipeline for single-cell hepatocyte-pathogen sequencing. Sub-populations of sexually committed parasite forms, previously thought to appear only during erythrocytic infection have now been identified. This groundbreaking insight into the Plasmodium life cycle can change our understanding of malaria transmission, yet it remains unknown how malaria parasites commit to these different developmental outcomes in hepatocytes. DEXES will test the hypothesis that Plasmodium liver infection outcomes depend upon the metabolic state of the host hepatocyte. This project will uncover the molecular mechanisms underpinning dormancy, relapsing and transmission of malaria parasites, and lay the groundwork for the future development of new therapies targeting the liver infection reservoirs.

Project details

Basic Science

Oct 2023 — Sep 2028

$2.16M

France