Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage.

Autor:	Stanway RR; Institute of Cell Biology, University of Bern, Bern 3012, Switzerland., Bushell E; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Molecular Infection Medicine Sweden (MIMS), Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden., Chiappino-Pepe A; Laboratory of Computational Systems Biotechnology, École Polytechnique Fédérale de Lausanne, EPFL, Lausanne 1015, Switzerland., Roques M; Institute of Cell Biology, University of Bern, Bern 3012, Switzerland., Sanderson T; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK., Franke-Fayard B; Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, Leiden University Medical Center (LUMC), Leiden 2333ZA, the Netherlands., Caldelari R; Institute of Cell Biology, University of Bern, Bern 3012, Switzerland., Golomingi M; Institute of Cell Biology, University of Bern, Bern 3012, Switzerland., Nyonda M; Department of Microbiology & Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland., Pandey V; Laboratory of Computational Systems Biotechnology, École Polytechnique Fédérale de Lausanne, EPFL, Lausanne 1015, Switzerland; Molecular Infection Medicine Sweden (MIMS), Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden., Schwach F; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK., Chevalley S; Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, Leiden University Medical Center (LUMC), Leiden 2333ZA, the Netherlands., Ramesar J; Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, Leiden University Medical Center (LUMC), Leiden 2333ZA, the Netherlands., Metcalf T; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK., Herd C; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK., Burda PC; Institute of Cell Biology, University of Bern, Bern 3012, Switzerland; Bernhard Nocht Institute for Tropical Medicine, Hamburg 20359, Germany., Rayner JC; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2, 0XY, UK., Soldati-Favre D; Department of Microbiology & Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland., Janse CJ; Leiden Malaria Research Group, Parasitology, Center of Infectious Diseases, Leiden University Medical Center (LUMC), Leiden 2333ZA, the Netherlands., Hatzimanikatis V; Laboratory of Computational Systems Biotechnology, École Polytechnique Fédérale de Lausanne, EPFL, Lausanne 1015, Switzerland., Billker O; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Molecular Infection Medicine Sweden (MIMS), Department of Molecular Biology, Umeå University, Umeå 901 87, Sweden. Electronic address: oliver.billker@umu.se., Heussler VT; Institute of Cell Biology, University of Bern, Bern 3012, Switzerland. Electronic address: volker.heussler@izb.unibe.ch.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2019 Nov 14; Vol. 179 (5), pp. 1112-1128.e26.
DOI:	10.1016/j.cell.2019.10.030
Abstrakt:	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. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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