title: Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii.
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.
authors.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.
authors.forename: Carl
authors.initials: C
authors.lastname: Song
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Chiasson
authors.forename: Nirvana
authors.initials: N
authors.lastname: Nursimulu
authors.forename: Stacy S
authors.initials: SS
authors.lastname: Hung
authors.forename: James
authors.initials: J
authors.lastname: Wasmuth
authors.forename: Michael E
authors.initials: ME
authors.lastname: Grigg
authors.forename: John
authors.initials: J
authors.lastname: Parkinson
mesh_terms: D000981:Antiprotozoal Agents / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000469:parasitology*; D005786:Gene Expression Regulation; D058507:Host Specificity; D006790:Host-Parasite Interactions; D006801:Humans; D060847:Metabolic Engineering; D053858:Metabolic Networks and Pathways; D008957:Models, Genetic; D011804:Quinolines / Q000494:pharmacology; D013045:Species Specificity; D014122:Toxoplasma / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D000981:Antiprotozoal Agents; D004164:Diphosphonates; D011804:Quinolines