Analysis of Nitric Oxide Synthase and Nitrotyrosine Expression in Human Pulmonary Tuberculosis

Choi, Hyung-Seok; Pradeep, Roshini; Chu, Hong Wei; Chan, Edward D.

doi:10.1164/rccm.2201023

Cited by 140 publications

(119 citation statements)

References 49 publications

(56 reference statements)

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“…Genome-wide association studies link NOS2 with an increased incidence of TB (4)(5)(6)(7)(8), although the expression and/or activity of iNOS resulting from these polymorphisms are unknown. Still other investigators reported that iNOS and NO production in TB patients correlates with less severe disease, and NO production by human alveolar MFs ex vivo inhibits mycobacterial growth (9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Rapovy¹,

Zhao²,

Bricker³

et al. 2015

The Journal of Immunology

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Microbicidal NO production is reliant on inducible NO synthase–mediated l-arginine metabolism in macrophages (MΦs). However, l-arginine supply can be restricted by arginase activity, resulting in inefficient NO output and inhibition of antimicrobial MΦ function. MΦs circumvent this by converting l-citrulline to l-arginine, thereby resupplying substrate for NO production. In this article, we define the metabolic signature of mycobacteria-infected murine MΦs supplied l-arginine, l-citrulline, or both amino acids. Using liquid chromatography–tandem mass spectrometry, we determined that l-arginine synthesized from l-citrulline was less effective as a substrate for arginase-mediated l-ornithine production compared with l-arginine directly imported from the extracellular milieu. Following Mycobacterium bovis bacillus Calmette–Guérin infection and costimulation with IFN-γ, we observed that MΦ arginase activity did not inhibit production of NO derived from l-citrulline, contrary to NO inhibition witnessed when MΦs were cultured in l-arginine. Furthermore, we found that arginase-expressing MΦs preferred l-citrulline over l-arginine for the promotion of antimycobacterial activity. We expect that defining the consequences of l-citrulline metabolism in MΦs will provide novel approaches for enhancing immunity, especially in the context of mycobacterial disease.

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confidence: 99%

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Rapovy¹,

Zhao²,

Bricker³

et al. 2015

The Journal of Immunology

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“…The high-output pathway of RNS production by host inducible nitric oxide synthase (iNOS) contributes to control of diverse infections (1,2), including tuberculosis (TB) (3,4), via impacts on both the pathogen and the host (5). Macrophages in the lungs of humans (6,7) and macaques (8) with TB express functional iNOS. Correlative evidence suggests that the action of iNOS may contribute to human control of TB (1,3,9,10).…”

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confidence: 99%

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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“…Two conditions frequently associated with latent TB in vivo are reduced oxygen tension and nitric oxide (NO) exposure (5,6). Both of these stimuli can induce reversible bacterial stasis in vitro (7,8), and both are encountered by bacilli in vivo (5,9,10). Further, although MTB requires oxygen for growth, it can survive without oxygen for surprisingly long periods of time (11,12).…”

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confidence: 99%

Two Sensor Kinases Contribute to the Hypoxic Response of Mycobacterium tuberculosis

Roberts

Liao

Wisedchaisri

et al. 2004

Journal of Biological Chemistry

233

246

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Current estimates indicate that nearly a third of the world's population is latently infected with Mycobacterium tuberculosis. Reduced oxygen tension and nitric oxide exposure are two conditions encountered by bacilli in vivo that may promote latency. In vitro exposure to hypoxia or nitric oxide results in bacterial stasis with concomitant induction of a 47-gene regulon controlled by the transcription factor DosR. In this report we demonstrate that both the dosS gene adjacent to dosR and another gene, dosT (Rv2027c), encode sensor kinases, each of which can autophosphorylate at a conserved histidine and then transfer phosphate to an aspartate residue of DosR. Mutant bacteria lacking both sensors are unable to activate expression of DosR-regulated genes. These data indicate that DosR/DosS/DosT comprise a two-component signaling system that is required for the M. tuberculosis genetic response to hypoxia and nitric oxide, two conditions that produce reversible growth arrest in vitro and may contribute to latency in vivo.Tuberculosis (TB) 1 has placed a heavy burden on the global community for centuries, earning such morbid nicknames as The White Plague and The Captain of the Men of Death (1). The causative agent, Mycobacterium tuberculosis (MTB), kills about 2 million people annually making it a leading cause of infectious death worldwide (2, 3). The success of MTB as a pathogen is closely linked with its capacity to persist for years or decades in humans in the absence of any clinical disease symptoms. Current estimates place the number of people latently infected with MTB at nearly 2 billion, or one-third of the Earth's population (3, 4). Eradicating this enormous reservoir of latently infected carriers is complicated by several factors, including the availability, cost, and length of drug therapy required for successful treatment of latent TB.Although TB has been studied for centuries, the triggers that promote and maintain latent infections are still obscure. Two conditions frequently associated with latent TB in vivo are reduced oxygen tension and nitric oxide (NO) exposure (5, 6). Both of these stimuli can induce reversible bacterial stasis in vitro (7,8), and both are encountered by bacilli in vivo (5, 9, 10). Further, although MTB requires oxygen for growth, it can survive without oxygen for surprisingly long periods of time (11,12). Still the evidence linking hypoxia and NO to latent TB in vivo remains circumstantial. Analysis of the MTB response to these factors is needed to define the role they may play in promoting and maintaining TB latency in humans.Previous reports identified a set of 47 MTB genes that are rapidly up-regulated in response to reduced oxygen tension or NO (8, 13). Among the MTB genes induced by hypoxia or exposure to NO is the putative two-component regulatory system dosR-dosS (also called devR-devS, Rv3133c/Rv3132c 2 ) (8, 13). In bacteria, two-component response regulator systems are an important means by which a variety of environmental signals are transduced into a phenotypic respo...

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Analysis of Nitric Oxide Synthase and Nitrotyrosine Expression in Human Pulmonary Tuberculosis

Cited by 140 publications

References 49 publications

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

Differential Requirements for l-Citrulline and l-Arginine during Antimycobacterial Macrophage Activity

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

Two Sensor Kinases Contribute to the Hypoxic Response of Mycobacterium tuberculosis

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