Nitrite impacts the survival of <i>Mycobacterium tuberculosis</i> in response to isoniazid and hydrogen peroxide

Cunningham‐Bussel, Amy; Bange, Franz; Nathan, Carl

doi:10.1002/mbo3.126

Cited by 23 publications

(27 citation statements)

References 49 publications

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“…1F). In both monolayer and bead culture, the cfus of Mtb recovered from the cultures were not significantly different for narG-deficient and WT Mtb (34).…”

Section: Mtb Respires Nitrate In Human Macrophages Cultured At Nonhypmentioning

confidence: 86%

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Nitrite produced byMycobacterium tuberculosisin human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression

Cunningham‐Bussel¹,

Zhang

Nathan³

2013

Proc. Natl. Acad. Sci. U.S.A.

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In high enough concentrations, such as produced by inducible nitric oxide synthase (iNOS), reactive nitrogen species (RNS) can kill Mycobacterium tuberculosis (Mtb). Lesional macrophages in macaques and humans with tuberculosis express iNOS, and mice need iNOS to avoid succumbing rapidly to tuberculosis. However, Mtb's own ability to produce RNS is rarely considered, perhaps because nitrate reduction to nitrite is only prominent in axenic Mtb cultures at oxygen tensions ≤1%. Here we found that cultures of Mtbinfected human macrophages cultured at physiologic oxygen tensions produced copious nitrite. Surprisingly, the nitrite arose from the Mtb, not the macrophages. Mtb responded to nitrite by ceasing growth; elevating levels of ATP through reduced consumption; and altering the expression of 120 genes associated with adaptation to acid, hypoxia, nitric oxide, oxidative stress, and iron deprivation. The transcriptomic effect of endogenous nitrite was distinct from that of nitric oxide. Thus, whether or not Mtb is hypoxic, the host expresses iNOS, or hypoxia impairs the action of iNOS, Mtb in vivo is likely to encounter RNS by producing nitrite. Endogenous nitrite may slow Mtb's growth and prepare it to resist host stresses while the pathogen waits for immunopathology to promote its transmission.

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“…1F). In both monolayer and bead culture, the cfus of Mtb recovered from the cultures were not significantly different for narG-deficient and WT Mtb (34).…”

Section: Mtb Respires Nitrate In Human Macrophages Cultured At Nonhypmentioning

confidence: 86%

“…Besides halting Mtb's growth, impairing its consumption of ATP, and altering its transcriptome, mycobacterial nitrite also markedly reduces Mtb's susceptibility to isoniazid (34). We do not know the major ATP-consuming pathway(s) in Mtb that function(s) in whole-cell lysates and that nitrite inhibits.…”

Section: Discussionmentioning

confidence: 98%

Nitrite produced byMycobacterium tuberculosisin human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression

Cunningham‐Bussel¹,

Zhang

Nathan³

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…These findings suggest a dual role for NarGHI in energy metabolism and in producing the mediator of an adaptive response to the intracellular environment. Endogenous nitrite production by M. tuberculosis reduces its sensitivity to isoniazid both within macrophages and in axenic culture, implicating NarGHI in intrinsic resistance to this antibiotic (40). However, the implications of these findings for pulmonary TB in humans remain unknown.…”

Section: Discussionmentioning

confidence: 99%

bis -Molybdopterin Guanine Dinucleotide Is Required for Persistence of Mycobacterium tuberculosis in Guinea Pigs

et al. 2015

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e Mycobacterium tuberculosis is able to synthesize molybdopterin cofactor (MoCo), which is utilized by numerous enzymes that catalyze redox reactions in carbon, nitrogen, and sulfur metabolism. In bacteria, MoCo is further modified through the activity of a guanylyltransferase, MobA, which converts MoCo to bis-molybdopterin guanine dinucleotide (bis-MGD), a form of the cofactor that is required by the dimethylsulfoxide (DMSO) reductase family of enzymes, which includes the nitrate reductase NarGHI. In this study, the functionality of the mobA homolog in M. tuberculosis was confirmed by demonstrating the loss of assimilatory and respiratory nitrate reductase activity in a mobA deletion mutant. This mutant displayed no survival defects in human monocytes or mouse lungs but failed to persist in the lungs of guinea pigs. These results implicate one or more bis-MGDdependent enzymes in the persistence of M. tuberculosis in guinea pig lungs and underscore the applicability of this animal model for assessing the role of molybdoenzymes in this pathogen.

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“…2, 3, and 4). Not only do these highly effective stress response strategies protect M. tuberculosis from host immunity, but the resulting changes in physiology also contribute to antibiotic tolerance, which precludes eradication of the infection (143)(144)(145)(146)(147)(148). The recalcitrance of M. tuberculosis in response to antibiotic therapy has led to an increase in drug-resistant M. tuberculosis infections to the point that we are not equipped to successfully battle the M. tuberculosis epidemic (2).…”

Section: Final Thoughtsmentioning

confidence: 99%

Mycobacterium tuberculosis Transcription Machinery: Ready To Respond to Host Attacks

2016

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Regulating responses to stress is critical for all bacteria, whether they are environmental, commensal, or pathogenic species. For pathogenic bacteria, successful colonization and survival in the host are dependent on adaptation to diverse conditions imposed by the host tissue architecture and the immune response. Once the bacterium senses a hostile environment, it must enact a change in physiology that contributes to the organism's survival strategy. Inappropriate responses have consequences; hence, the execution of the appropriate response is essential for survival of the bacterium in its niche. Stress responses are most often regulated at the level of gene expression and, more specifically, transcription. This minireview focuses on mechanisms of regulating transcription initiation that are required by Mycobacterium tuberculosis to respond to the arsenal of defenses imposed by the host during infection. In particular, we highlight how certain features of M. tuberculosis physiology allow this pathogen to respond swiftly and effectively to host defenses. By enacting highly integrated and coordinated gene expression changes in response to stress, M. tuberculosis is prepared for battle against the host defense and able to persist within the human population.T he survival of any organism relies on its ability to sense and respond to changes in its environment. For bacteria, stress responses are primarily mediated through the regulation of gene expression. By integrating multiple molecular approaches to gene regulation, pathogenic bacteria are able to orchestrate conditionspecific patterns that promote survival and pathogenesis in the face of a strong immune response. This minireview focuses on mechanisms of transcription regulation required for stress responses in one of the most successful and deadly pathogens in the world, Mycobacterium tuberculosis. M. tuberculosis has coexisted with humans for Ͼ50,000 years (1) and continues to cause more than 1.5 million deaths a year (2). The coevolution of M. tuberculosis with the human host response to infection has resulted in a pathogen that is specialized for long-term infection in people. Tuberculosis is a complex disease that requires the bacteria to multiply within phagocytes, survive extracellularly in hypoxic and necrotic granulomas, and endure a robust immune response to persist in the host. During infection, the host immune response restrains M. tuberculosis from proliferating by imposing a battery of defenses, including reactive oxygen and nitrogen stress, hypoxia, acid stress, genotoxic stress, cell surface stress, and starvation (3). Despite this onslaught of attacks, M. tuberculosis is able to persist for the lifetime of the host, indicating that this pathogen has highly effective molecular mechanisms to resist host-inflicted damage. In order to enact these defenses and facilitate this specialized lifestyle, M. tuberculosis executes a complex, interconnected web of stress responses that rely on changes in gene expression. In fact, M. tuberculosis is well suite...

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Nitrite impacts the survival of Mycobacterium tuberculosis in response to isoniazid and hydrogen peroxide

Cited by 23 publications

References 49 publications

Nitrite produced byMycobacterium tuberculosisin human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression

Nitrite produced byMycobacterium tuberculosisin human macrophages in physiologic oxygen impacts bacterial ATP consumption and gene expression

bis -Molybdopterin Guanine Dinucleotide Is Required for Persistence of Mycobacterium tuberculosis in Guinea Pigs

Mycobacterium tuberculosis Transcription Machinery: Ready To Respond to Host Attacks

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