Reductive Stress in Microbes: Implications for Understanding Mycobacterium tuberculosis Disease and Persistence

Farhana, Aisha; Guidry, Loni; Srivastava, Anup; Singh, Amit; Hondalus, Mary K.; Steyn, Adrie J. C.

doi:10.1016/b978-0-12-381045-8.00002-3

Cited by 55 publications

(60 citation statements)

References 290 publications

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“…Interestingly, this form of WhiB3 is able to undergo further post-translational modifications in response to redox stress, modulating DNA-binding activity 85, 103 . M. tuberculosis experiences redox stress during infection as a result of NADPH production following fatty acid β-oxidation 103, 104 . Reducing equivalents such as NADPH can undergo autoxidation, leading to increased ROS production 105 .…”

Section: Iron-sulfur Cluster Regulators and Their Role In Bacterial Pmentioning

confidence: 99%

Bacterial iron–sulfur cluster sensors in mammalian pathogens

Miller

Auerbuch

2015

Metallomics

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Iron-sulfur clusters act as important cofactors for a number of transcriptional regulators in bacteria, including many mammalian pathogens. The sensitivity of iron-sulfur clusters to iron availability, oxygen tension, and reactive oxygen and nitrogen species enables bacteria to use such regulators to adapt their gene expression profiles rapidly in response to changing environmental conditions. In this review, we discuss how the [4Fe-4S] or [2Fe-2S] cluster-containing regulators FNR, Wbl, aconitase, IscR, NsrR, SoxR, and AirSR contribute to bacterial pathogenesis through control of both metabolism and classical virulence factors. In addition, we briefly review mammalian iron homeostasis as well as oxidative/nitrosative stress to provide context for understanding the function of bacterial iron-sulfur cluster sensors in different niches within the host.

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Section: Iron-sulfur Cluster Regulators and Their Role In Bacterial Pmentioning

confidence: 99%

Bacterial iron–sulfur cluster sensors in mammalian pathogens

Miller

Auerbuch

2015

Metallomics

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“…Although technically challenging, obtaining the crystal structure of any Wbl protein would significantly contribute to the field. The identification of Mtb WhiB3 as a metabolic redox sensor (41) is particularly interesting as the concept of reductive stress emerged from these findings (18).…”

Section: Discussionmentioning

confidence: 99%

“…This leads to the generation of high concentrations of NAD(P)H during the conversion of fatty acids to acetate and propionate. The accumulation of high levels of NAD(P)H causes reductive stress in Mtb (18,40). Furthermore, host-generated free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) are also capable of disturbing Mtb redox balance.…”

Section: Fig 1 Redox Machinery Of Mtbmentioning

confidence: 99%

“…WhiB3 also senses or responds to fluctuating levels of reducing equivalents (NADH) that are generated by the TCA cycle (respiration), and NADPH that accumulates during (boxidation of host fatty acids. If not properly balanced, the bacillus will experience reductive stress (18). As a result, WhiB3 channels these excess reducing equivalents into virulence lipid anabolic pathways, which requires NADPH as cofactor.…”

Section: Figmentioning

confidence: 99%

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Mycobacterium tuberculosisWhiB3: A Novel Iron–Sulfur Cluster Protein That Regulates Redox Homeostasis and Virulence

Saini

Farhana²,

Steyn³

2012

Antioxidants & Redox Signaling

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Significance: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), can persist in a latent state for decades without causing overt disease. Since latent Mtb is refractory to current antimycobacterial drugs, the discovery and characterization of the biological mechanisms controlling the entry, maintenance, and emergence from latent infection is critical to the development of novel clinical therapies. Recent Advances: Recently, Mtb WhiB3, a member of the family of intracellular iron-sulfur (Fe-S) cluster proteins has emerged as a redox sensor and effector molecule controlling several aspects of Mtb virulence. WhiB3 was shown to contain a 4Fe-4S cluster that specifically reacts with important host gases (O 2 and NO), and exogenous and endogenous metabolic signals to maintain redox balance. Notably, the concept of reductive stress emerged from studies on WhiB3. Critical Issues: The detailed mechanism of how WhiB3 functions as an intracellular redox sensor is unknown. Sustaining Mtb redox balance is particularly important since the bacilli encounter a large number of redox stressors during infection, and because several antimycobacterial prodrugs are effective only upon bioreductive activation in the mycobacterial cytoplasm. Future Directions: How Mtb WhiB3 monitors its internal and external surroundings and modulates endogenous oxido-reductive pathways which in turn alter Mtb signal transduction, nucleic acid and protein synthesis, and enzymatic activation, is mostly unexplored. Modern expression, metabolomic and proteomic technologies should provide fresh insights into these yet unanswered questions. Antioxid. Redox Signal. 16, 687-697.

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“…Some experts believe that mycobacteria acquire iron from the iron-binding proteins of the host's own transferrin/ferritin. These bacteria capture iron carriers to obtain iron from the host by releasing a type of iron called exochelin (Farhana et al, 2010;Wilson et al, 2011). Exochelin transfers iron onto mycobacterium auxin (in mycobacterium cell wall).…”

Section: Discussionmentioning

confidence: 99%

Relationship among C-reactive protein, iron status, oxidative stress, and pulmonary tuberculosis

Sun¹,

Yang²,

Ren³

et al. 2012

Afr. J. Pharm. Pharmacol.

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This study aims to assess the effects of acute tuberculosis and drug treatment on oxidative stress markers [malondialdehyde (MDA) and total antioxidant status (TAS)], C-reactive protein (CRP), and body iron index. A total of 20 patients with active tuberculosis (treatment group) and 50 healthy subjects (control group) were selected. MDA, TAS, serum CRP, serum iron, serum total iron binding capacity, transferrin saturation, and serum ferritin in the treatment (before and after) and control groups were evaluated. After two months of treatment, MDA, CRP, and ferritin significantly decreased, whereas TAS, serum iron, and transferrin saturation significantly increased. Serum total iron binding force demonstrated a significant effect. In the first two months of treatment, oxidative stress was significantly improved, and the inflammation was under control. CRP levels increased inflammatory response in tuberculosis. Drug therapy significantly improved the iron status of patients with anemia of chronic inflammation.

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Reductive Stress in Microbes: Implications for Understanding Mycobacterium tuberculosis Disease and Persistence

Cited by 55 publications

References 290 publications

Bacterial iron–sulfur cluster sensors in mammalian pathogens

Bacterial iron–sulfur cluster sensors in mammalian pathogens

Mycobacterium tuberculosisWhiB3: A Novel Iron–Sulfur Cluster Protein That Regulates Redox Homeostasis and Virulence

Relationship among C-reactive protein, iron status, oxidative stress, and pulmonary tuberculosis

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