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Cell Host Microbe. 2020 Feb 12;27(2):290-306.e11. doi: 10.1016/j.chom.2020.01.002. Epub 2020 Jan 27.

Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism.

Author information

1
Department of Microbiology & Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland.
2
Laboratory of Computational Systems Biotechnology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.
3
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
4
School of Pharmaceutical Sciences Geneva-Lausanne (EPGL), Geneva 1211, Switzerland; Mass Spectrometry Core Facility (MZ 2.0), University of Geneva, Geneva 1211, Switzerland.
5
Institute of Parasitology, University of Zürich, Zürich 8057, Switzerland.
6
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
7
Department of Microbiology & Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland. Electronic address: dominique.soldati-favre@unige.ch.

Abstract

To survive and proliferate in diverse host environments with varying nutrient availability, the obligate intracellular parasite Toxoplasma gondii reprograms its metabolism. We have generated and curated a genome-scale metabolic model (iTgo) for the fast-replicating tachyzoite stage, harmonized with experimentally observed phenotypes. To validate the importance of four metabolic pathways predicted by the model, we have performed in-depth in vitro and in vivo phenotyping of mutant parasites including targeted metabolomics and CRISPR-Cas9 fitness screening of all known metabolic genes. This led to unexpected insights into the remarkable flexibility of the parasite, addressing the dependency on biosynthesis or salvage of fatty acids (FAs), purine nucleotides (AMP and GMP), a vitamin (pyridoxal-5P), and a cofactor (heme) in both the acute and latent stages of infection. Taken together, our experimentally validated metabolic network leads to a deeper understanding of the parasite's biology, opening avenues for the development of therapeutic intervention against apicomplexans.

KEYWORDS:

CRISPR-Cas9 screen; Toxoplasma gondii; bradyzoite; fatty acid biosynthesis; heme biosynthesis; metabolic network; metabolism; synthetic lethality; tachyzoite; vitamin B6

PMID:
31991093
DOI:
10.1016/j.chom.2020.01.002

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