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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.

SUBMITTER: Song C

PROVIDER: S-EPMC4039375 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii.

Song Carl C Chiasson Melissa A MA Nursimulu Nirvana N Hung Stacy S SS Wasmuth James J Grigg Michael E ME Parkinson John J

Molecular systems biology 20131119

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. ...[more]

PMID: 24247825

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Project description:Many RNA modifications have been detected in rRNA, tRNA and small noncoding RNA (sncRNA) as well as in low-abundance RNA species such mRNA. Although RNA modifications play roles in many cellular and biological processes in various domains of life, knowledge about the diversity and role of RNA modifications in Toxoplasma gondii is limited. In this study, RNA modifications in three T. gondii strains (RH type I, PRU type II, and VEG type III) with distinct virulence abilities were determined by liquid chromatography-tandem mass spectrometry. We compared the levels of modifications of four nucleotides in tRNA and sncRNA, characterized RNA modification patterns of different T. gondii strains, and determined the diversity of RNA modifications. We detected and quantified 22 modified nucleosides in both tRNA and sncRNA. Significant differences in the diversity of the modified nucleosides were found between the three T. gondii strains. RNA modifications were correlated with the expression of many T. gondii virulence proteins. Some of the identified modifications (e.g., 2'-O-methylinosine, pseudouridine) play a role in mediating the host-parasite interaction. These results provide novel insight into the global modifications in tRNA and sncRNA, and the diversity of RNA modifications between T. gondii strains with different virulence backgrounds. IMPORTANCE Although RNA modifications play roles in many cellular and developmental processes in various domains of life, knowledge about the patterns and functions of RNA modifications in T. gondii is limited. Here, a quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach was used to study global RNA modifications in T. gondii strains of distinct virulence backgrounds. We quantified 22 modified nucleosides in both tRNA and sncRNA. Significant T. gondii strain-specific differences in RNA modifications were detected. More tRNA modifications correlated with T. gondii virulence proteins than sncRNA modifications. RNA modifications were significantly correlated with virulence proteins. Our data provide the first comprehensive profiling of the modifications tRNA and sncRNA in T. gondii, expanding the diversity of RNA modifications in this parasite and suggesting new regulators for modulating its virulence.

Project description:BACKGROUND: Toxoplasma gondii (T. gondii) is a very successful parasite that can infect virtually all warm blooded animals with a worldwide distribution. It causes a large range of clinical manifestations in both humans and domesticated animals. In addition, marked biological differences exist among T. gondii strains in the pathogenicity and geographical distribution. Molecular epidemiology studies primarily based on restriction fragment length polymorphism (RFLP) method revealed that three main types are predominant in North America and Europe, whereas other diverse genotypes are found in other parts of the world. Microsatellite (MS) as a type of genetic marker has been widely used in many organisms. Limited MS genotyping, however, to fingerprint T. gondii isolates has been reported and little is known about the MS data of the strains predominantly prevalent in China. METHODS: Genotyping of twenty-eight Chinese T. gondii isolates were performed using 15 MS markers located on 12 different chromosomes. Results were analyzed in terms of population structure by a Bayesian statistical approach. Phylogenetic analysis was obtained from a Neighbor-Net phylogenetic network. The virulence analyses of some representative isolates were determined by inoculation of mice and cell invasion assays. The gene expressions of some virulence-associated factors (VFs) were performed by quantitative real-time PCR (qRT- PCR). RESULTS: Three haplogroups were clustered among the 28 isolates although minor genetic differences were found within haplogroups. The majority of strains belong to one haplogroup corresponding to the previously described Chinese 1 type (ToxoDB#9). Phylogenetic networks uncovered a limited diversity of T. gondii strains and the virulence differs in the strains sharing the same genotype. No remarkable difference, however, was noted in the tested VFs except for dense granule protein3 (GRA3), which was found to have a higher expression in low virulent TgCtwh6 (Wh6) strain than that in high virulent TgCtwh3 (Wh3) strain. CONCLUSION: The profile of microsatellite typing data from Chinese T. gondii strains revealed a limited genetic diversity and the selected VFs and phylogenetic network analyses displayed less divergence, although the strain virulence differs in the Chinese 1 type of T. gondii predominantly prevalent in China.

Dataset Information

Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii.

Publications

Metabolic reconstruction identifies strain-specific regulation of virulence in Toxoplasma gondii.

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