Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii.
Identifieur interne : 000D35 ( Main/Exploration ); précédent : 000D34; suivant : 000D36Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii.
Auteurs : Carl Song [Canada] ; Melissa A. Chiasson ; Nirvana Nursimulu ; Stacy S. Hung ; James Wasmuth ; Michael E. Grigg ; John ParkinsonSource :
- Molecular systems biology [ 1744-4292 ] ; 2013.
English descriptors
- KwdEn :
- Antiprotozoal Agents (pharmacology), Diphosphonates (pharmacology), Drug Resistance (drug effects), Fibroblasts (cytology), Fibroblasts (parasitology), Gene Expression Regulation, Host Specificity, Host-Parasite Interactions, Humans, Metabolic Engineering, Metabolic Networks and Pathways, Models, Genetic, Quinolines (pharmacology), Species Specificity, Toxoplasma (drug effects), Toxoplasma (genetics), Toxoplasma (metabolism), Toxoplasma (pathogenicity), Virulence.
- MESH :
- chemical , pharmacology : Antiprotozoal Agents, Diphosphonates, Quinolines.
- cytology : Fibroblasts.
- drug effects : Drug Resistance, Toxoplasma.
- genetics : Toxoplasma.
- metabolism : Toxoplasma.
- parasitology : Fibroblasts.
- pathogenicity : Toxoplasma.
- Gene Expression Regulation, Host Specificity, Host-Parasite Interactions, Humans, Metabolic Engineering, Metabolic Networks and Pathways, Models, Genetic, Species Specificity, Virulence.
Abstract
Increasingly, metabolic potential is proving to be a critical determinant governing a pathogen's virulence as well as its capacity to expand its host range. To understand the potential contribution of metabolism to strain-specific infectivity differences, we present a constraint-based metabolic model of the opportunistic parasite, Toxoplasma gondii. Dominated by three clonal strains (Type I, II, and III demonstrating distinct virulence profiles), T. gondii exhibits a remarkably broad host range. Integrating functional genomic data, our model (which we term as iCS382) reveals that observed strain-specific differences in growth rates are driven by altered capacities for energy production. We further predict strain-specific differences in drug susceptibilities and validate one of these predictions in a drug-based assay, with a Type I strain demonstrating resistance to inhibitors that are effective against a Type II strain. We propose that these observed differences reflect an evolutionary strategy that allows the parasite to extend its host range, as well as result in a subsequent partitioning into discrete strains that display altered virulence profiles across different hosts, different organs, and even cell types.
DOI: 10.1038/msb.2013.62
PubMed: 24247825
Affiliations:
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Chiasson</name></author><author><name sortKey="Nursimulu, Nirvana" sort="Nursimulu, Nirvana" uniqKey="Nursimulu N" first="Nirvana" last="Nursimulu">Nirvana Nursimulu</name></author><author><name sortKey="Hung, Stacy S" sort="Hung, Stacy S" uniqKey="Hung S" first="Stacy S" last="Hung">Stacy S. Hung</name></author><author><name sortKey="Wasmuth, James" sort="Wasmuth, James" uniqKey="Wasmuth J" first="James" last="Wasmuth">James Wasmuth</name></author><author><name sortKey="Grigg, Michael E" sort="Grigg, Michael E" uniqKey="Grigg M" first="Michael E" last="Grigg">Michael E. Grigg</name></author><author><name sortKey="Parkinson, John" sort="Parkinson, John" uniqKey="Parkinson J" first="John" last="Parkinson">John Parkinson</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2013">2013</date><idno type="RBID">pubmed:24247825</idno><idno type="pmid">24247825</idno><idno type="doi">10.1038/msb.2013.62</idno><idno type="wicri:Area/PubMed/Corpus">000838</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000838</idno><idno type="wicri:Area/PubMed/Curation">000838</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000838</idno><idno type="wicri:Area/PubMed/Checkpoint">000838</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000838</idno><idno type="wicri:Area/Ncbi/Merge">001618</idno><idno type="wicri:Area/Ncbi/Curation">001618</idno><idno type="wicri:Area/Ncbi/Checkpoint">001618</idno><idno type="wicri:Area/Main/Merge">000D46</idno><idno type="wicri:Area/Main/Curation">000D35</idno><idno type="wicri:Area/Main/Exploration">000D35</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii.</title><author><name sortKey="Song, Carl" sort="Song, Carl" uniqKey="Song C" first="Carl" last="Song">Carl Song</name><affiliation wicri:level="4"><nlm:affiliation>1] Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>1] Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Chiasson, Melissa A" sort="Chiasson, Melissa A" uniqKey="Chiasson M" first="Melissa A" last="Chiasson">Melissa A. Chiasson</name></author><author><name sortKey="Nursimulu, Nirvana" sort="Nursimulu, Nirvana" uniqKey="Nursimulu N" first="Nirvana" last="Nursimulu">Nirvana Nursimulu</name></author><author><name sortKey="Hung, Stacy S" sort="Hung, Stacy S" uniqKey="Hung S" first="Stacy S" last="Hung">Stacy S. Hung</name></author><author><name sortKey="Wasmuth, James" sort="Wasmuth, James" uniqKey="Wasmuth J" first="James" last="Wasmuth">James Wasmuth</name></author><author><name sortKey="Grigg, Michael E" sort="Grigg, Michael E" uniqKey="Grigg M" first="Michael E" last="Grigg">Michael E. Grigg</name></author><author><name sortKey="Parkinson, John" sort="Parkinson, John" uniqKey="Parkinson J" first="John" last="Parkinson">John Parkinson</name></author></analytic><series><title level="j">Molecular systems biology</title><idno type="eISSN">1744-4292</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiprotozoal Agents (pharmacology)</term><term>Diphosphonates (pharmacology)</term><term>Drug Resistance (drug effects)</term><term>Fibroblasts (cytology)</term><term>Fibroblasts (parasitology)</term><term>Gene Expression Regulation</term><term>Host Specificity</term><term>Host-Parasite Interactions</term><term>Humans</term><term>Metabolic Engineering</term><term>Metabolic Networks and Pathways</term><term>Models, Genetic</term><term>Quinolines (pharmacology)</term><term>Species Specificity</term><term>Toxoplasma (drug effects)</term><term>Toxoplasma (genetics)</term><term>Toxoplasma (metabolism)</term><term>Toxoplasma (pathogenicity)</term><term>Virulence</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiprotozoal Agents</term><term>Diphosphonates</term><term>Quinolines</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Fibroblasts</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Drug Resistance</term><term>Toxoplasma</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Toxoplasma</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Toxoplasma</term></keywords><keywords scheme="MESH" qualifier="parasitology" xml:lang="en"><term>Fibroblasts</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>Toxoplasma</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Gene Expression Regulation</term><term>Host Specificity</term><term>Host-Parasite Interactions</term><term>Humans</term><term>Metabolic Engineering</term><term>Metabolic Networks and Pathways</term><term>Models, Genetic</term><term>Species Specificity</term><term>Virulence</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Increasingly, metabolic potential is proving to be a critical determinant governing a pathogen's virulence as well as its capacity to expand its host range. To understand the potential contribution of metabolism to strain-specific infectivity differences, we present a constraint-based metabolic model of the opportunistic parasite, Toxoplasma gondii. Dominated by three clonal strains (Type I, II, and III demonstrating distinct virulence profiles), T. gondii exhibits a remarkably broad host range. Integrating functional genomic data, our model (which we term as iCS382) reveals that observed strain-specific differences in growth rates are driven by altered capacities for energy production. We further predict strain-specific differences in drug susceptibilities and validate one of these predictions in a drug-based assay, with a Type I strain demonstrating resistance to inhibitors that are effective against a Type II strain. We propose that these observed differences reflect an evolutionary strategy that allows the parasite to extend its host range, as well as result in a subsequent partitioning into discrete strains that display altered virulence profiles across different hosts, different organs, and even cell types.</div></front></TEI><affiliations><list><country><li>Canada</li></country><region><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><noCountry><name sortKey="Chiasson, Melissa A" sort="Chiasson, Melissa A" uniqKey="Chiasson M" first="Melissa A" last="Chiasson">Melissa A. Chiasson</name><name sortKey="Grigg, Michael E" sort="Grigg, Michael E" uniqKey="Grigg M" first="Michael E" last="Grigg">Michael E. Grigg</name><name sortKey="Hung, Stacy S" sort="Hung, Stacy S" uniqKey="Hung S" first="Stacy S" last="Hung">Stacy S. Hung</name><name sortKey="Nursimulu, Nirvana" sort="Nursimulu, Nirvana" uniqKey="Nursimulu N" first="Nirvana" last="Nursimulu">Nirvana Nursimulu</name><name sortKey="Parkinson, John" sort="Parkinson, John" uniqKey="Parkinson J" first="John" last="Parkinson">John Parkinson</name><name sortKey="Wasmuth, James" sort="Wasmuth, James" uniqKey="Wasmuth J" first="James" last="Wasmuth">James Wasmuth</name></noCountry><country name="Canada"><region name="Ontario"><name sortKey="Song, Carl" sort="Song, Carl" uniqKey="Song C" first="Carl" last="Song">Carl Song</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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