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 (Arg ->His) in the 4.2 domain of RpoV, the principal sigma factor in 515 Mycobacterium bovis, is attenuating. Mice infected with Mtb?whiB3 showed significantly longer survival times than mice infected with the wild type Mtb. In addition, the lungs of Mtb?whiB3-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 Mtb?whiB3. These studies will characterize WhiB3 as a potential target for interventions. The University of Alabama at Birmingham (UAB) is Alabama's largest employer, with more than 18,000 faculty and staff at the university and in the health system, and is responsible for 52,900 full-time equivalent jobs within the university and the community. Eight in every 100 jobs in the Birmingham area, and 2.8 jobs in every 100 jobs in Alabama, are related to UAB. UAB's overall economic impact in the Birmingham metro area exceeds $3 billion annually. Consistent with ARRA goals, this application will create or retain ~7 jobs.
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.
|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|
|Wang, Yong; Jin, Tong Huan; Farhana, Aisha et al. (2014) Exposure to cigarette smoke impacts myeloid-derived regulatory cell function and exacerbates airway hyper-responsiveness. Lab Invest 94:1312-25|
|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|
|Regev, Doron; Surolia, Ranu; Karki, Suman et al. (2012) Heme oxygenase-1 promotes granuloma development and protects against dissemination of mycobacteria. Lab Invest 92:1541-52|
|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|
|Farhana, Aisha; Guidry, Loni; Srivastava, Anup et al. (2010) Reductive stress in microbes: implications for understanding Mycobacterium tuberculosis disease and persistence. Adv Microb Physiol 57:43-117|