Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism
Name
1-s2.0-S193131282030041X-mmc9-1.pdf
Description
Accepted version
Size
23.08 MB
Format
Adobe PDF
Checksum (MD5)
5f10274ce4bd7ec0b911ca1f063a3427
Author(s)
Krishnan, Aarti
Kloehn, Joachim
Lunghi, Matteo
Chiappino-Pepe, Anush
Waldman, Benjamin S
Nicolas, Damien
Varesio, Emmanuel
Hehl, Adrian
Lourido, Sebastian
Hatzimanikatis, Vassily
Date Issued
2020
Journal
Cell Host and Microbe
Publisher
Elsevier BV
Version
Author's final manuscript
Abstract
© 2020 Elsevier Inc. 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/J.CHOM.2020.01.002
