Modeling Phenotypic Metabolic Adaptations of Mycobacterium Tuberculosis H37Rv Under Hypoxia

PLoS Comput Biol. 2012;8(9):e1002688. doi: 10.1371/journal.pcbi.1002688. Epub 2012 Sep 13.

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 of the enzymes catalyzing the related metabolic reactions.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptation, Physiological / physiology*
  • Bacterial Proteins / metabolism*
  • Computer Simulation
  • Models, Biological*
  • Mycobacterium tuberculosis / physiology*
  • Oxygen / metabolism*
  • Proteome / metabolism*
  • Signal Transduction / physiology*

Substances

  • Bacterial Proteins
  • Proteome
  • Oxygen

Grant support

This project was funded in part by a competitive In-house Laboratory Independent Research (ILIR) award by the U.S. Army Assistant Secretary of the Army for Acquisition, Logistics, and Technology (ASAALT). The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army or the U.S. Department of Defense. This paper has been approved for public release with unlimited distribution. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.