Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments.

Anubhav Srivastava,Michael P Barrett,Malcolm J Mcconville,Katie R Hughes,Konstantina Georgiou,Nisha Philip,James I Macrae,Darren J Creek,Andrew P Waters,Audrey Ragan Odom

doi:10.1371/journal.ppat.1006094

Anubhav Srivastava, Michael P Barrett + Show 8 more

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https://doi.org/10.1371/journal.ppat.1006094

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Abstract

Malaria parasites (Plasmodium spp.) encounter markedly different (nutritional) environments during their complex life cycles in the mosquito and human hosts. Adaptation to these different host niches is associated with a dramatic rewiring of metabolism, from a highly glycolytic metabolism in the asexual blood stages to increased dependence on tricarboxylic acid (TCA) metabolism in mosquito stages. Here we have used stable isotope labelling, targeted metabolomics and reverse genetics to map stage-specific changes in Plasmodium berghei carbon metabolism and determine the functional significance of these changes on parasite survival in the blood and mosquito stages. We show that glutamine serves as the predominant input into TCA metabolism in both asexual and sexual blood stages and is important for complete male gametogenesis. Glutamine catabolism, as well as key reactions in intermediary metabolism and CoA synthesis are also essential for ookinete to oocyst transition in the mosquito. These data extend our knowledge of Plasmodium metabolism and point towards possible targets for transmission-blocking intervention strategies. Furthermore, they highlight significant metabolic differences between Plasmodium species which are not easily anticipated based on genomics or transcriptomics studies and underline the importance of integration of metabolomics data with other platforms in order to better inform drug discovery and design.

Highlights

Malaria remains a major public health problem with more than 214 million new cases each year and 438,000 deaths world-wide
We explored the metabolic capacity of different developmental stages of the malaria parasite to determine carbon source utilization in different host niches and whether any stage-specific switches in metabolism could be exploited in new therapies aimed at eradicating malaria
In this study we have utilized a combination of metabolomic and reverse genetic approaches to investigate the metabolic changes that occur in key insect stages of the experimentally tractable species P. berghei and the potential impact of these changes on parasite infection in the mosquito. We find that these stages are highly sensitive to disruptions in multiple pathways in central carbon metabolism including the tricarboxylic acid (TCA) cycle, the utilisation of glutamine as a carbon source, intermediary carbon metabolism and coenzyme A (CoA) synthesis

Summary

Introduction

Malaria remains a major public health problem with more than 214 million new cases each year and 438,000 deaths world-wide. Increasing resistance to artemisinin threatens to undermine existing malaria control programs [2] and there remains an ongoing need to develop new therapeutics with a particular focus on drugs that target different parasite developmental stages responsible for pathogenesis and transmission via the mosquito vector. Glucose consumption by Plasmodium-infected RBC increases 10-fold and these stages rely primarily on glycolysis for energy generation [3,4,5,6,7]. Notwithstanding their dependence on glycolysis, asexual blood stages maintain a single, poorly cristate mitochondrion [8] and are dependent on electron transport chain (ETC) activity for the re-oxidation of inner membrane dehydrogenases and pyrimidine biosynthesis [9]. Despite the essentiality of the mitochondrion, operation of the TCA cycle is not required for intra-erythrocytic growth of P. falciparum [10,11,14,15]

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