Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism
© 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 st...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2021
|
| Online Access: | https://hdl.handle.net/1721.1/136312 |
| _version_ | 1826202010035159040 |
|---|---|
| author | Krishnan, Aarti Kloehn, Joachim Lunghi, Matteo Chiappino-Pepe, Anush Waldman, Benjamin S Nicolas, Damien Varesio, Emmanuel Hehl, Adrian Lourido, Sebastian Hatzimanikatis, Vassily Soldati-Favre, Dominique |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Krishnan, Aarti Kloehn, Joachim Lunghi, Matteo Chiappino-Pepe, Anush Waldman, Benjamin S Nicolas, Damien Varesio, Emmanuel Hehl, Adrian Lourido, Sebastian Hatzimanikatis, Vassily Soldati-Favre, Dominique |
| author_sort | Krishnan, Aarti |
| collection | MIT |
| description | © 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. |
| first_indexed | 2024-09-23T12:00:44Z |
| format | Article |
| id | mit-1721.1/136312 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:00:44Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1363122023-12-22T20:16:59Z Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism Krishnan, Aarti Kloehn, Joachim Lunghi, Matteo Chiappino-Pepe, Anush Waldman, Benjamin S Nicolas, Damien Varesio, Emmanuel Hehl, Adrian Lourido, Sebastian Hatzimanikatis, Vassily Soldati-Favre, Dominique Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research © 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. 2021-10-27T20:34:50Z 2021-10-27T20:34:50Z 2020 2021-07-21T16:58:31Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136312 en 10.1016/J.CHOM.2020.01.002 Cell Host and Microbe Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Elsevier BV Other repository |
| spellingShingle | Krishnan, Aarti Kloehn, Joachim Lunghi, Matteo Chiappino-Pepe, Anush Waldman, Benjamin S Nicolas, Damien Varesio, Emmanuel Hehl, Adrian Lourido, Sebastian Hatzimanikatis, Vassily Soldati-Favre, Dominique Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism |
| title | Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism |
| title_full | Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism |
| title_fullStr | Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism |
| title_full_unstemmed | Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism |
| title_short | Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism |
| title_sort | functional and computational genomics reveal unprecedented flexibility in stage specific toxoplasma metabolism |
| url | https://hdl.handle.net/1721.1/136312 |
| work_keys_str_mv | AT krishnanaarti functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism AT kloehnjoachim functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism AT lunghimatteo functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism AT chiappinopepeanush functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism AT waldmanbenjamins functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism AT nicolasdamien functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism AT varesioemmanuel functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism AT hehladrian functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism AT louridosebastian functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism AT hatzimanikatisvassily functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism AT soldatifavredominique functionalandcomputationalgenomicsrevealunprecedentedflexibilityinstagespecifictoxoplasmametabolism |