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Accession Number ADA571134
Title Modeling Phenotypic Metabolic Adaptations of Mycobacterium tuberculosis H37Rv under Hypoxia.
Publication Date Sep 2012
Media Count 16p
Personal Author A. Wallqvist J. Reifman X. Fang
Abstract The ability to adapt to different conditions is key for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), to successfully infect human hosts. Adaptations allow the organism to evade the host immune responses during acute infections and persist for an extended period of time during the latent infectious stage. In latently infected individuals estimated to include one-third of the human population, the organism exists in a variety of metabolic states, which impedes the development of a simple strategy for controlling or eradicating this disease. Direct knowledge of the metabolic states of M. tuberculosis in patients would aid in the management of the disease as well as in forming the basis for developing new drugs and designing more efficacious drug cocktails. Here, we propose an in silico approach to create state-specific models based on readily available gene expression data. The coupling of differential gene expression data with a metabolic network model allowed us to characterize the metabolic adaptations of M. tuberculosis H37Rv to hypoxia. Given the microarray data for the alterations in gene expression, our model predicted reduced oxygen uptake, ATP production changes, and a global change from an oxidative to a reductive tricarboxylic acid (TCA) program. Alterations in the biomass composition indicated an increase in the cell wall metabolites required for cell-wall growth, as well as heightened accumulation of triacylglycerol in preparation for a low-nutrient, low metabolic activity life style. In contrast, the gene expression program in the deletion mutant of dosR, which encodes the immediate hypoxic response regulator, failed to adapt to low-oxygen stress. Our predictions were compatible with recent experimental observations of M. tuberculosis activity under hypoxic and anaerobic conditions. Importantly, alterations in the flow and accumulation of a particular metabolite were not necessarily directly linked to differential gene expression.
Keywords Adaptation(Physiology)
Arrays
Biomass
Cell wall
Gene expression
Hypoxia
Metabolic adaptation
Microarrays
Mycobacterium tuberculosis


 
Source Agency Non Paid ADAS
NTIS Subject Category 57E - Clinical Medicine
57K - Microbiology
Corporate Author Army Medical Research and Materiel Command (Provisional), Fort Detrick, MD. Biotechnology High Performance Computing Software Applications Inst.
Document Type Journal article
Title Note Journal article.
NTIS Issue Number 1315
Contract Number N/A

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