Dataset Information

Cellular Growth Arrest and Persistence from Enzyme Saturation.

ABSTRACT: Metabolic efficiency depends on the balance between supply and demand of metabolites, which is sensitive to environmental and physiological fluctuations, or noise, causing shortages or surpluses in the metabolic pipeline. How cells can reliably optimize biomass production in the presence of metabolic fluctuations is a fundamental question that has not been fully answered. Here we use mathematical models to predict that enzyme saturation creates distinct regimes of cellular growth, including a phase of growth arrest resulting from toxicity of the metabolic process. Noise can drive entry of single cells into growth arrest while a fast-growing majority sustains the population. We confirmed these predictions by measuring the growth dynamics of Escherichia coli utilizing lactose as a sole carbon source. The predicted heterogeneous growth emerged at high lactose concentrations, and was associated with cell death and production of antibiotic-tolerant persister cells. These results suggest how metabolic networks may balance costs and benefits, with important implications for drug tolerance.

SUBMITTER: Ray JC

PROVIDER: S-EPMC4820279 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Cellular Growth Arrest and Persistence from Enzyme Saturation.

Ray J Christian J JC Wickersheim Michelle L ML Jalihal Ameya P AP Adeshina Yusuf O YO Cooper Tim F TF Balázsi Gábor G

PLoS computational biology 20160324 3

Metabolic efficiency depends on the balance between supply and demand of metabolites, which is sensitive to environmental and physiological fluctuations, or noise, causing shortages or surpluses in the metabolic pipeline. How cells can reliably optimize biomass production in the presence of metabolic fluctuations is a fundamental question that has not been fully answered. Here we use mathematical models to predict that enzyme saturation creates distinct regimes of cellular growth, including a ph ...[more]

PMID: 27010473

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Project description:Francisella tularensis is one of the most virulent bacterial pathogens known and causes the disease tularemia, which can be fatal if untreated. This zoonotic and intracellular pathogen is exposed to diverse environmental and host stress factors that require an appropriate response to survive. However, the stress tolerance mechanisms used by F. tularensis to persist are not fully understood. To address this aspect, we evaluated the highly conserved universal stress protein (Usp) that is encoded by a single-copy gene in F. tularensis, unlike the majority of other bacterial pathogens that produce several to many Usp homologs. We determined that the F. tularensis Usp transcript is unusually stable with a half-life of over 30 minutes, and that usp transcript and protein levels remained abundant when exposed to low pH, nutrient deprivation, hydrogen peroxide, and paraquat. Of these and other stress conditions evaluated, the F. tularensis Δusp mutant only exhibited reduced survival relative to the wild type during stationary phase and exposure to paraquat, a highly toxic compound that generates superoxide anions and other free radicals. Comparison of transcript levels in untreated and paraquat-treated F. tularensis wild type and Δusp indicated that Usp contributes to enhanced expression of antioxidant defense genes, oxyR and katG. In summary, the high abundance and stability of Usp provide prompt protection during extended periods of growth arrest and free radical exposure, promoting F. tularensis persistence. We propose that F. tularensis Usp contributes to an adaptive response that prolongs viability and increases the longevity of this zoonotic pathogen in the environment.ImportanceFrancisella tularensis is classified as a Tier 1 select agent due to the low infectious dose, ease of transmission, and potential use as a bioweapon. To better understand the stress defense mechanisms that contribute to the ability of this highly virulent pathogen to persist, we evaluated the conserved F. tularensis universal stress protein (Usp). We show that F. tularensis Usp is unusually stable and remains abundant, regardless of the stress conditions tested, differing from other bacterial Usp homologs. We also determined that F. tularensis Usp enhances the expression of several critical antioxidant defense genes and increases survival during paraquat exposure and growth arrest. Determining the factors that promote F. tularensis persistence in the environment is needed to prevent tularemia transmission.

Dataset Information

Cellular Growth Arrest and Persistence from Enzyme Saturation.

Publications

Cellular Growth Arrest and Persistence from Enzyme Saturation.

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