Metabolic Profiling of Lung Granuloma in Mycobacterium tuberculosis Infected Guinea Pigs: Ex vivo H-1 Magic Angle Spinning NMR Studies

Department of Microbiology, Immunology and Pathology, Colorado State University, Campus Delivery 1682, Fort Collins, Colorado 80523-1682, United States.
Journal of Proteome Research (Impact Factor: 5). 07/2011; 10(9):4186-95. DOI: 10.1021/pr2003352
Source: PubMed

ABSTRACT A crucial and distinctive feature of tuberculosis infection is that Mycobacterium tuberculosis (Mtb) resides in granulomatous lesion at various stages of disease development and necrosis, an aspect that is little understood. We used a novel approach, applying high resolution magic angle spinning nuclear magnetic resonance spectroscopy (HRMAS NMR) directly to infected tissues, allowing us to study the development of tuberculosis granulomas in guinea pigs in an untargeted manner. Significant up-regulation of lactate, alanine, acetate, glutamate, oxidized and the reduced form of glutathione, aspartate, creatine, phosphocholine, glycerophosphocholine, betaine, trimethylamine N-oxide, myo-inositol, scyllo-inositol, and dihydroxyacetone was clearly visualized and was identified as the infection progressed. Concomitantly, phosphatidylcholine was down-regulated. Principal component analysis of NMR data revealed clear group separation between infected and uninfected tissues. These metabolites are suggestive of utilization of alternate energy sources by the infiltrating cells that generate much of the metabolites in the increasingly necrotic and hypoxic developing granuloma through the glycolytic, pentose phosphate, and tricarboxylic acid pathways. The most relevant changes seen are, surprisingly, very similar to metabolic changes seen in cancer during tumor development.

Download full-text


Available from: Bagganahalli S Somashekar, Sep 02, 2014
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The tuberculosis (TB) bacillus, Mycobacterium tuberculosis, is a facultative intracellular pathogen that multiplies inside macrophages, in which it resides within a specialized compartment, the phagosome, where nutrient sources are likely limited. A number of studies provided compelling evidence that M. tuberculosis has the ability to exploit host-derived carbon sources, such as triglycerides, cholesterol and glucose, and to proliferate inside host cells (McKinney et al., 2000;Pandey and Sassetti, 2008;Daniel et al., 2011;Marrero et al., 2013). In addition to carbon, nitrogen is an essential constituent of all living organisms. As compared to carbon requirements, little is known about the nature of nitrogen-containing molecules utilized by the TB bacillus during infection. We recently discovered that nitrogen incorporation from exogenous aspartate is required for host colonization by M. tuberculosis (Gouzy et al., 2013). This study highlights, for the first time, the potential of amino acids, and aspartate in particular, as a major nitrogen reservoir supporting M. tuberculosis virulence in vivo. It also opens a series of questions to be addressed in the future.
    Frontiers in Cellular and Infection Microbiology 01/2013; 3:68. DOI:10.3389/fcimb.2013.00068 · 2.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Experimental animals in biomedical research provide insights into disease mechanisms and models for determining the efficacy and safety of new therapies and for discovery of corresponding biomarkers. Although mouse and rat models are most widely used, observations in these species cannot always be faithfully extrapolated to human patients. Thus, a number of domestic species are additionally used in specific disease areas. This review summarizes the most important applications of domestic animal models and emphasizes the new possibilities genetic tailoring of disease models, specifically in pigs, provides.
    Reproduction in Domestic Animals 08/2012; 47 Suppl 4:59-71. DOI:10.1111/j.1439-0531.2012.02056.x · 1.18 Impact Factor
  • Source
    Understanding Tuberculosis - Analyzing the Origin of Mycobacterium Tuberculosis Pathogenicity, 02/2012; , ISBN: 978-953-307-942-4