Malaria is one of the most devastating global human infectious diseases, caused by endoparasitic Plasmodium parasites, with nearly a quarter of a billion annual cases worldwide. The most virulent of the human infectious species, Plasmodium falciparum, accounts for 90% of all malaria related deaths. The Plasmodium parasite shares a highly interconnected metabolism with its host red blood cell, rapidly consuming and exchanging nutrients in order to develop and replicate. While asexual Plasmodium parasites thrive within human red blood cells, they are obligated to differentiate into their sexual form to facilitate mosquito transmission and complete their lifecycle. Blocking the transmission of Plasmodium falciparum gametocytes from human host to mosquito vector is widely considered a major control point in preventing the spread of malaria. Despite the therapeutic potential of this life cycle stage, little is known about the mechanisms or requirements guiding gametocyte commitment and development. This lack of understanding has hindered the development of gametocytocidal compounds, which are in great demand but are currently in short supply, inefficacious across all gametocyte stages, or have negative side effects. Therefore, targeting transmission is an integral approach to the eradication of malaria since it is the critical link between the human host and mosquito vector. The research proposed herein will use a two-fold state-of-the-art mass spectrometry-based metabolomics approach to obtain a fingerprint of the small molecules underlying this obligate transformation. Tandem liquid chromatography-mass spectrometry (LC-MS) will be used to understand the global metabolome changes that accompany gametocyte commitment and maturation during this 14-day process. Additionally, 13C- and 15N-isotope labeled compounds will be used to profile metabolite flux and utilization in Plasmodium parasites undergoing sexual differentiation.
Aim 1 will identify the active metabolic processes within a developing and differentiated gametocyte, which will serve as a blueprint for further studies. Pharmacologic intervention will be used in Aim 2 to perturb cellular metabolism and define gametocytocidal modes of action, complementing this global metabolomics-based approach.
Despite increased global efforts to eradicate malaria, strategies have been more effective at reducing the number of deaths (29%) than the number of cases (8%) since 2000. This translates to ~3.4 billion people being at risk of malaria infection, with 207 million reported infections and ~625,000 deaths in 2012 alone. This project is geared toward combating malaria by defining the metabolic processes that allow sexual stage development and ultimately host to vector transmission, a critical juncture with potentially profound therapeutic strategies for reducing the spread of infected mosquitoes and limiting propagation of drug resistance.
| Allman, Erik L; Painter, Heather J; Samra, Jasmeet et al. (2016) Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways. Antimicrob Agents Chemother 60:6635-6649 |
