Sexual Conversion in Plasmodium falciparum – an Integrated Approach to Characterize and Target the Achilles’ Heel of Malaria Parasites

Sexual conversion initiates the production of gametocytes in the human malaria parasite Plasmodium falciparum. After maturation, these sexual precursor cells are the only parasite form capable of establishing an infection in the mosquito vector. Sexual conversion and proper gametocyte development, hence, are essential for transmission of the disease. Asexual reproduction, on the other hand, is required for establishing chronic infections and production of a continuous source of transmission stages. Finding the right balance between asexual growth and gametocyte production is thus essential for the malaria parasite to achieve its ultimate goal of disease transmission.It has been known for many years that malaria parasites are able to vary the rate at which sexual conversion is initiated and gametocyte production is generally elevated in response to unfavorable environmental conditions, including high parasite density and drug treatment. Whereas recent findings started to shed light on the molecular mechanisms that control the sexual conversion process itself, it remains unclear how parasites are able to sense environmental changes and how this information is translated into the observed phenotypic plasticity. Recently, two studies, one of which was performed in the host laboratory, identified the existence of microvesicle mediated cell-to-cell communication in Plasmodium. The authors revealed a direct link between the uptake of these membranous structures and the induction of sexual conversion in recipient cells. Potentially, parasites are using microvesicles as a proxy for population density. As a current fellow of the Early Postdoc.Mobility program, the investigator is investigating this cellular communication pathway in order to understand how the parasite can regulate the balance between growth and transmission on a population level.  To this end the researcher have identified and characterized functional miRNA complexes in microvesicles, and have developed a high throughput-compatible assay that allows to systematically probe the effect of perturbations, including microvesicle presence and environmental/host factors, on sexual conversion. With these approaches, the investigator anticipate to gain information about the signaling pathway(s) that modulate(s) sexual conversion. Complementing ongoing efforts, the researcher will functionally characterize selected candidate molecules of the identified pathways using reverse genetics and state of the art sequencing techniques. The anticipated results will be of high importance to understand the mechanisms that underlie sexual conversion in malaria parasites and, hence, may become instrumental for the development of future transmission-blocking strategies.

Project details

Basic Science

Aug 2015 — Jan 2017

$77,551

Switzerland