M. tuberculosis (Mtb) is one of the leading causes of death worldwide and claims millions of lives annually. Approximately ~1.7 billion people worldwide are asymptomatically infected with the tubercle bacillus and constitute a major impediment to worldwide public health control measures. Previous work had shown that a point mutation (Arg515->His) in the 4.2 domain of RpoV, the principal sigma factor in Mycobacterium bovis, is attenuating. Mice infected with MtbwhiB3 showed significantly longer survival times than mice infected with the wild type Mtb. In addition, the lungs of MtbwhiB3-infected mice appeared much less adversely affected. Recent studies have shown that WhiB3 is a 4Fe-4S cluster protein and initiates the metabolic switchover to the preferred in vivo carbon source, fatty acids. We hypothesize that WhiB3 is an intracellular redox sensor that maintains redox homeostasis. To better understand the mechanism of this physiological event, we will identify the WhiB3 amino acids necessary for effective iron-sulfur (Fe-S) reconstitution, and use electron paramagnetic resonance spectroscopy (EPR) to characterize these mutated proteins. We will use genome-wide expression profiling to examine the contribution of WhiB3 in maintaining redox homeostasis, and analyze the metabolite profile of MtbwhiB3. These studies will characterize WhiB3 as a potential target for interventions that may abolish virulence, but not growth. These studies will also provide insight into understanding how Mtb subvert host immunity.

Public Health Relevance

The ability of small numbers of Mycobacterium tuberculosis (Mtb) to lay dormant in humans without causing disease is central to the biology of the disease. We will examine how Mtb enters a persistent state, and hope to translate this knowledge into new interventions to reduce tuberculosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacterial Pathogenesis Study Section (BACP)
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Lacourciere, Karen A
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University of Alabama Birmingham
Schools of Medicine
United States
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Saini, Vikram; Cumming, Bridgette M; Guidry, Loni et al. (2016) Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis. Cell Rep 14:572-585
Lamprecht, Dirk A; Finin, Peter M; Rahman, Md Aejazur et al. (2016) Turning the respiratory flexibility of Mycobacterium tuberculosis against itself. Nat Commun 7:12393
Chinta, Krishna C; Saini, Vikram; Glasgow, Joel N et al. (2016) The emerging role of gasotransmitters in the pathogenesis of tuberculosis. Nitric Oxide 59:28-41
Gopal, Radha; Monin, Leticia; Torres, Diana et al. (2013) S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. Am J Respir Crit Care Med 188:1137-46
Saini, Vikram; Farhana, Aisha; Steyn, Adrie J C (2012) Mycobacterium tuberculosis WhiB3: a novel iron-sulfur cluster protein that regulates redox homeostasis and virulence. Antioxid Redox Signal 16:687-97
Saini, Vikram; Farhana, Aisha; Glasgow, Joel N et al. (2012) Iron sulfur cluster proteins and microbial regulation: implications for understanding tuberculosis. Curr Opin Chem Biol 16:45-53
Chawla, Manbeena; Parikh, Pankti; Saxena, Alka et al. (2012) Mycobacterium tuberculosis WhiB4 regulates oxidative stress response to modulate survival and dissemination in vivo. Mol Microbiol 85:1148-65
Farhana, Aisha; Saini, Vikram; Kumar, Ashwani et al. (2012) Environmental heme-based sensor proteins: implications for understanding bacterial pathogenesis. Antioxid Redox Signal 17:1232-45
Kumar, Ashwani; Farhana, Aisha; Guidry, Loni et al. (2011) Redox homeostasis in mycobacteria: the key to tuberculosis control? Expert Rev Mol Med 13:e39
Mai, Deborah; Jones, Jennifer; Rodgers, John W et al. (2011) A screen to identify small molecule inhibitors of protein-protein interactions in mycobacteria. Assay Drug Dev Technol 9:299-310

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