Stage-specific changes in plasmodium metabolism required for differentiation and adaptation to different host and vector environments

Srivastava, A., Philip, N., Hughes, K. R., Georgiou, K., MacRae, J. I., Barrett, M. P. , Creek, D. J., McConville, M. J. and Waters, A. P. (2016) Stage-specific changes in plasmodium metabolism required for differentiation and adaptation to different host and vector environments. PLoS Pathogens, 12(12), e1006094. (doi:10.1371/journal.ppat.1006094) (PMID:28027318) (PMCID:PMC5189940)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hughes, Dr Katie and Waters, Professor Andy and Georgiou, Miss Konstantina and Srivastava, Mr Anubhav and Philip, Dr Nisha and Barrett, Professor Michael
Authors: Srivastava, A., Philip, N., Hughes, K. R., Georgiou, K., MacRae, J. I., Barrett, M. P., Creek, D. J., McConville, M. J., and Waters, A. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright © 2016 Srivastava et al
First Published:First published in PLoS Pathogens 12(12): e1006094
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
466861Conditional translational repression: a core regulatory mechanism of gene expression during development of the malaria parasite.Andrew WatersWellcome Trust (WELLCOME)083811/Z/07/ZIII - PARASITOLOGY
690321Gene expression in Plasmodium parasites: the molecular mechanics of gametocytogenesis (and variant transcription of genes)Andrew WatersWellcome Trust (WELLCOME)107046/Z/15/ZIII - PARASITOLOGY