Metabolic reconstruction identifies strain‐specific regulation of virulence in <i>Toxoplasma gondii</i>

Song, Carl Yulun; Chiasson, Melissa A; Nursimulu, Nirvana; Hung, Stacy; Wasmuth, James D.; Grigg, Michael E.; Parkinson, John

doi:10.1038/msb.2013.62

Cited by 49 publications

(48 citation statements)

References 84 publications

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“…Increasingly, metabolic potential is considered a critical element governing a pathogen's virulence as well as its ability to survive in its host (6,13,16,(40)(41)(42)(43)(44). Here we show that the S. aureus CcpE protein captures changes in citrate levels and transforms them into various cellular responses.…”

Section: Discussionmentioning

confidence: 78%

Metabolic sensor governing bacterial virulence in Staphylococcus aureus

Ding¹,

Liu

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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An effective metabolism is essential to all living organisms, including the important human pathogen Staphylococcus aureus. To establish successful infection, S. aureus must scavenge nutrients and coordinate its metabolism for proliferation. Meanwhile, it also must produce an array of virulence factors to interfere with host defenses. However, the ways in which S. aureus ties its metabolic state to its virulence regulation remain largely unknown. Here we show that citrate, the first intermediate of the tricarboxylic acid (TCA) cycle, binds to and activates the catabolite control protein E (CcpE) of S. aureus. Using structural and site-directed mutagenesis studies, we demonstrate that two arginine residues (Arg145 and Arg256) within the putative inducer-binding cavity of CcpE are important for its allosteric activation by citrate. Microarray analysis reveals that CcpE tunes the expression of 126 genes that comprise about 4.7% of the S. aureus genome. Intriguingly, although CcpE is a major positive regulator of the TCA-cycle activity, its regulon consists predominantly of genes involved in the pathogenesis of S. aureus. Moreover, inactivation of CcpE results in increased staphyloxanthin production, improved ability to acquire iron, increased resistance to whole-blood-mediated killing, and enhanced bacterial virulence in a mouse model of systemic infection. This study reveals CcpE as an important metabolic sensor that allows S. aureus to sense and adjust its metabolic state and subsequently to coordinate the expression of virulence factors and bacterial virulence.Staphylococcus aureus | metabolism | iron acquisition | virulence gene expression | bacterial virulence

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Section: Discussionmentioning

confidence: 78%

Metabolic sensor governing bacterial virulence in Staphylococcus aureus

Ding¹,

Liu

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…FBA investigations of pathogenic organisms have been used to search for novel drug targets and have pointed to potential metabolic targets not affected by current therapeutics, such as amino acid production or fatty acid metabolism [53][54][55][56][57][58][59][60]. Oberhardt and colleagues have constructed a genome-based model of metabolism and transport in P. aeruginosa [61], and used flux balance analysis (FBA) with transcript data from two CF clinical strains to investigate P. aeruginosa's metabolic capabilities and potential metabolic changes during prolonged infection [62].…”

mentioning

confidence: 99%

Metabolic flux analyses of Pseudomonas aeruginosa cystic fibrosis isolates

Opperman

Shachar‐Hill

2016

Metabolic Engineering

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“…Therefore, we felt the inclusion of these additional covariates to be important for improved generalisation of the results. Finally, strains of T. gondii differ in virulence (Song et al 2013), potentially limiting comparison of our findings with other studies in that the data sets we used did not enable us to determine strain of T. gondii.…”

Section: Discussionmentioning

confidence: 85%

No association between latent toxoplasmosis and multiple body measures in U.S. adults

et al. 2016

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Toxoplasma gondii (Nicolle et Manceaux, 1908) is an intracellular parasite that can cause ongoing latent infection persisting for the duration of a non-definitive host's life. Affecting approximately one-third of the world's population, latent toxoplasmosis has been associated with neuropsychological outcomes and a previous report suggested an association between latent toxoplasmosis and adult height. Given the large number of people with latent toxoplasmosis and its potential associations with human height, we sought to better understand the association between latent toxoplasmosis and human morphology by evaluating seropositivity for T. gondii and multiple body measures reported in the National Health and Nutrition Examination Survey III (NHANES III) and in the more recent continuous NHANES data sets from the United States Centers for Disease Control and Prevention for which data on T. gondii are available. In these analyses, latent toxoplasmosis was not associated with any of the body measures assessed in the NHANES datasets even after taking into account interactions between latent toxoplasmosis and testosterone suggesting that in these samples, latent toxoplasmosis is not associated with adult morphology including height.

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

Abstract: 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.

Cited by 49 publications

References 84 publications

Metabolic sensor governing bacterial virulence in Staphylococcus aureus

Metabolic sensor governing bacterial virulence in Staphylococcus aureus

Metabolic flux analyses of Pseudomonas aeruginosa cystic fibrosis isolates

No association between latent toxoplasmosis and multiple body measures in U.S. adults

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