Periodic Reporting for period 1 - MalariaSex (The molecular mechanisms of sex determination in a malaria parasite)
Okres sprawozdawczy: 2021-09-01 do 2023-08-31
Plasmodium parasites are the causative agent of malaria - a severe disease and global health burden with an estimated 241 million cases and 627’000 deaths in 2020. While the clinical symptoms of malaria arise from successive rounds of asexual replication in the blood of the vertebrate host, transmission of the disease to the mosquito vector is facilitated by a small subset of blood-stage parasites entering sexual development. The ability of the parasite to produce fertile female and male gametocytes in an optimal ratio is critical for their reproductive success and disease transmission. Therefore, understanding the molecular mechanisms of sexual development and sex determination in these medically relevant organisms is key to the design of new transmission-blocking strategies and a broader knowledge of how Plasmodium parasites regulate vital life cycle decisions.
A recent genetic screen and transcriptomic study have identified a small panel of genes critical for the origin of male gametocytes. Knock-outs of these genes result in skewed gametocyte sex ratios and impact the parasite’s reproduction capacity. However, despite the discovery of genetic factors facilitating sex ratio determination and sexual differentiation, the molecular mechanisms underpinning these processes remain unclear as the functions of the proteins encoded by the identified genes are unknown. This research proposal focuses on uncovering the functions of three maleness-determining candidate genes by applying a combination of biochemical, genetic, and cell biological techniques. The obtained results will elucidate the molecular mechanisms facilitating sex, and thus transmission, of malaria parasites.
A recent genetic screen and transcriptomic study have identified a small panel of genes critical for the origin of male gametocytes. Knock-outs of these genes result in skewed gametocyte sex ratios and impact the parasite’s reproduction capacity. However, despite the discovery of genetic factors facilitating sex ratio determination and sexual differentiation, the molecular mechanisms underpinning these processes remain unclear as the functions of the proteins encoded by the identified genes are unknown. This research proposal focuses on uncovering the functions of three maleness-determining candidate genes by applying a combination of biochemical, genetic, and cell biological techniques. The obtained results will elucidate the molecular mechanisms facilitating sex, and thus transmission, of malaria parasites.
The main focus of the covered funding period has been the development of parasite lines, protein characterization assays, and genetic modification tools in the rodent malaria parasite model Plasmodium berghei, with the goal of utilizing the developed protocols and parasite lines to characterize the function of the three maleness-determining candidate genes. New P. berghei parasite lines, harboring protein tags on the three-maleness candidate genes have been established and were subsequently used to determine the protein-protein interaction networks of each maleness-determining candidate factor.
The work carried out to date in this project has provided novel insights into the functional context of three proteins involved in sex ratio determination in a malaria parasite and further laid the technical groundwork for future experiments unlocking the question of how sex ratio determination is achieved in these ancient eukaryotic parasites. The outcome of this and future works will help to understand the molecular mechanisms of sex ratio and sex determination in malaria parasites, which is not only of importance for basic biology research but also for the design of new disease transmission interventions.