Unraveling the nature of the sexual merozoite - an elusive stage in the malaria parasite cycle

• Applicant: Dr. Tobias Spielmann
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 550310007

Malaria remains a major global public health threat, with over 200 million new infections and 600000 fatal cases in 2023. A major pillar of ongoing elimination efforts is to block parasite transmission from man to mosquito. Such efforts are all the more critical as resistance against the the most effiicent antimalarial currently in use, Artemisinin (ART) is spreading fast and has now reached Africa. Malaria transmission is initiated when a subset of asexually replicating blood stage parasites produce sexual progeny, or gametocytes, the only form capable of onward transmission to mosquitoes. Marti and Spielmann labs investigate host parasite interactions, mechanisms of drug resistance and the biology of malaria transmission in the most virulent human malaria parasite, Plasmodium falciparum. Our previoius work revealed that gametocytes primarily develop in the hematopoietic niche of the bone marrow, in particular in reticulocytes (immature red blood cells), suggesting preferential invasion of the sexual merozoite (the invasive red blood stage) into this host cell. Recent studies have indicated higher rates of gametocyte production by ART resistant parasites and reduced ART susceptibility in the gametocyte stage compared to asexual blood stage parasites. Our own combined preliminary data suggest a complex interplay between the mode of action of ART, genetic determinants of malaria transmission and the function of Kelch13, the major target of ART resistance. Our labs have developed a series of tools that enable detection and purification of both sexual and asexual parasites for subsequent analysis. Here we propose systematic phenotypic and functional characterisation of sexual merozoites and the resulting early gametocyte stages with respect to their invasion and nutrient/drug uptake properties. We have three specific aims: i) Define the interactome of invasion and nutrient uptake determinants in sexually committed schizonts and sexual rings, ii) interrogate red blood cell invasion of sexual merozoites and iii) interrogate nutrient uptake and ART susceptibility in sexually committed schizonts and sexual stages. Specific questions include: Is there a unique invasion pathway for sexual merozoites? What are the receptor ligand interactions underlying sexual merozoite invasion? What are the nutrient requirements of sexual rings and early-stage gametocytes and does this influence ART susceptibility in resistant and sensitive parasites? To answer these questions, we will combine biochemical assays to define protein complexes with high resolution imaging, a variety of phenotypic assays and reverse genetics for the functional characterization of target proteins in the context of sexual merozoite invasion and gametocyte endocytosis including ART uptake and activity. These experiments will close a major knowledge gap in the malaria transmission cycle and provide a rationale for novel interventions, in particular against ART resistant parasites.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Cooperation Partners: Dr. Christof Grüring; Professor Dr. Matthias Marti