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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Nov 16

PMID 31730853

Citations 55

Authors

Rebecca R Stanway

Ellen Bushell

Anush Chiappino-Pepe

Magali Roques

Theo Sanderson

Blandine Franke-Fayard

Reto Caldelari

Murielle Golomingi

Mary Nyonda

Vikash Pandey

Frank Schwach

Severine Chevalley

Jai Ramesar

Tom Metcalf

Colin Herd

Paul-Christian Burda

Julian C Rayner

Dominique Soldati-Favre

Chris J Janse

Vassily Hatzimanikatis

Oliver Billker

Volker T Heussler

Affiliations

Soon will be listed here.

Abstract

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.

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