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Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
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2019 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 179, no 5, p. 1112-1128.e1-e15Article in journal (Refereed) Published
Abstract [en]

Plasmodium gene functions in mosquito and liver stages remain poorly characterized due to limitations in the throughput of phenotyping at these stages. To fill this gap, we followed more than 1,300 barcoded P. berghei mutants through the life cycle. We discover 461 genes required for efficient parasite transmission to mosquitoes through the liver stage and back into the bloodstream of mice. We analyze the screen in the context of genomic, transcriptomic, and metabolomic data by building a thermodynamic model of P. berghei liver-stage metabolism, which shows a major reprogramming of parasite metabolism to achieve rapid growth in the liver. We identify seven metabolic subsystems that become essential at the liver stages compared with asexual blood stages: type II fatty acid synthesis and elongation (FAE), tricarboxylic acid, amino sugar, heme, lipoate, and shikimate metabolism. Selected predictions from the model are individually validated in single mutants to provide future targets for drug development.

Place, publisher, year, edition, pages
Elsevier, 2019. Vol. 179, no 5, p. 1112-1128.e1-e15
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Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-165826DOI: 10.1016/j.cell.2019.10.030ISI: 000496914200010PubMedID: 31730853OAI: oai:DiVA.org:umu-165826DiVA, id: diva2:1379063
Funder
Wellcome trust, 206194/Z/17/ZKnut and Alice Wallenberg Foundation
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Available from: 2019-12-16 Created: 2019-12-16 Last updated: 2019-12-18Bibliographically approved

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Bushell, EllenPandey, VikashBillker, Oliver
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