Metabolic reconstruction identifies strain‐specific regulation of virulence in Toxoplasma gondii

Molecular Systems Biology

Carl Song²  Melissa A Chiasson¹  Nirvana Nursimulu²  Stacy S Hung²  James Wasmuth²  Michael E Grigg¹ 

[1] Molecular Parasitology Section, Laboratory of Parasitic Diseases, NIAID, National Institutes of Health, Bethesda, MD, USA;Program in Molecular Structure and Function, The Hospital for Sick Children, Toronto, Ontario, Canada

关键词: flux balance analysis;    metabolic reconstruction;    strain differences;    Toxoplasma gondii;   

DOI  :  10.1038/msb.2013.62

来源: Wiley

【 摘 要 】

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.

Synopsis

The first metabolic reconstruction for Toxoplasma gondii ‘iCS382’ is presented. Model simulations and drug assays identified strain-specific differences in growth rates that may reflect an evolutionary strategy, potentiating broad host range.

• The first metabolic reconstruction of Toxoplasma gondii was generated, capturing current knowledge of the parasite's metabolic capabilities.
• Strain-specific differences in the expression of enzymes in energy production pathways were predicted to impact growth rates and may reflect an underlying evolutionary strategy that allows the parasite to broaden its host range.
• The validated strain-specific sensitivity to enzyme knockouts demonstrates the need to consider the diversity of parasite strains during the development of novel therapeutic approaches.

【 授权许可】

CC BY-NC-SA   
Copyright © 2013 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.