Last Updated: 06/11/2023
The secret lives of parasites in hepatocytes during malaria infection
Objectives
- Identification of the hepatocyte subpopulation preferred by distinct P. falciparum strains from different geographical origins for development.
- Identification of cellular host factor(s) for optimal parasite development in preferred hepatocytes.
- Determining the biological function(s) of the identified host factor(s) for developing parasites and infected hepatocytes.
Radboud University Medical Center (Radboudumc), The Netherlands
Malaria remains a significant parasitic disease transmitted by mosquitoes resulting in over 220 million clinical cases and half a million deaths annually. With increasing resistance of parasites and mosquitoes to current interventions, there is a pressing need to provide innovative strategies to combat and eradicate this disease. Plasmodium falciparum (Pf) parasites are responsible for the highest disease burden. During the initial asymptomatic liver stages, intracellular parasites undergo massive replication before release into the circulation, associated with the emergence of clinical symptoms and complications. Knowledge of Pf-liver stage biology is incomplete but essential for rational design of drugs/vaccines. Research is restricted to the use of in vitro liver cultures with low parasite infection rates (<0.1-5%) or imperfect animal models. This knowledge gap will be addressed by focusing on the cross-talk between parasite and hepatocytes during this complex and dynamic phase of parasite development in the human host. Fresh primary human hepatocytes will be used as the most physiological source and hepatic organoids for genetic manipulation. Preliminary data show parasites developing preferentially in particular hepatocyte subpopulations characterized by the exclusive presence of the enzyme, glutamine synthetase, as well as in liver organoids. Transcriptomic and metabolomic profiles of the permissive host cell will allow for genetic engineering of stable hepatic organoid cell-lines highly permissive to parasites as novel tools for Pf-liver stage studies. This project will provide novel insight into the conditions required for parasite development in liver which can be exploited for development of novel intervention strategies.
Jan 2020 — Aug 2023
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