scholarly journals Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages.

1992 ◽  
Vol 175 (4) ◽  
pp. 1111-1122 ◽  
Author(s):  
J Chan ◽  
Y Xing ◽  
R S Magliozzo ◽  
B R Bloom
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Antimycobacterial Activity ◽  
Oxygen Radical ◽  
Reactive Nitrogen ◽  
Parental Line ◽  
Murine Macrophage ◽  
Macrophage Cell ◽  
Oxygen Intermediates ◽  
Murine Macrophages ◽  
Reactive Nitrogen Intermediates

Tuberculosis remains one of the major infectious causes of morbidity and mortality in the world, yet the mechanisms by which macrophages defend against Mycobacterium tuberculosis have remained obscure. Results from this study show that murine macrophages, activated by interferon gamma, and lipopolysaccharide or tumor necrosis factor alpha, both growth inhibit and kill M. tuberculosis. This antimycobacterial effect, demonstrable both in murine macrophage cell lines and in peritoneal macrophages of BALB/c mice, is independent of the macrophage capacity to generate reactive oxygen intermediates (ROI). Both the ROI-deficient murine macrophage cell line D9, and its ROI-generating, parental line J774.16, expressed comparable antimycobacterial activity upon activation. In addition, the oxygen radical scavengers superoxide dismutase (SOD), catalase, mannitol, and diazabicyclooctane had no effect on the antimycobacterial activity of macrophages. These findings, together with the results showing the relative resistance of M. tuberculosis to enzymatically generated H2O2, suggest that ROI are unlikely to be significantly involved in killing M. tuberculosis. In contrast, the antimycobacterial activity of these macrophages strongly correlates with the induction of the L-arginine-dependent generation of reactive nitrogen intermediates (RNI). The effector molecule(s) that could participate in mediating this antimycobacterial function are toxic RNI, including NO, NO2, and HNO2, as demonstrated by the mycobacteriocidal effect of acidified NO2. The oxygen radical scavenger SOD adventitiously perturbs RNI production, and cannot be used to discriminate between cytocidal mechanisms involving ROI and RNI. Overall, our results provide support for the view that the L-arginine-dependent production of RNI is the principal effector mechanism in activated murine macrophages responsible for killing and growth inhibiting virulent M. tuberculosis.

scholarly journals Mycobacterium tuberculosis CDC1551 Is Resistant to Reactive Nitrogen and Oxygen Intermediates In Vitro

2002 ◽  
Vol 70 (7) ◽  
pp. 3965-3968 ◽  
Author(s):  
Marcia A. Firmani ◽  
Lee W. Riley
Keyword(s):  
Hydrogen Peroxide ◽  
Mycobacterium Tuberculosis ◽  
The Other ◽  
Reactive Nitrogen ◽  
Reactive Oxygen Intermediates ◽  
Oxygen Intermediates ◽  
Large Outbreak ◽  
Biological Phenotype ◽  
Reactive Nitrogen Intermediates

ABSTRACT Resistance to reactive oxygen intermediates and reactive nitrogen intermediates in vitro of a clinical isolate of Mycobacterium tuberculosis (CDC1551) that caused a large outbreak of tuberculosis was compared to that of M. tuberculosis strains CB3.3, H37Rv, H37Ra, Erdman, RJ2E, C.C. 13, and C.C. 22 as well as M. bovis strains Ravenel and BCG. CDC1551 and CB3.3 were significantly more resistant to both hydrogen peroxide (H2O2) and acidified sodium nitrite than were the other strains tested. This biological phenotype may serve as an in vitro marker for clinical strains of M. tuberculosis likely to cause a large outbreak of tuberculosis.

scholarly journals Response to Reactive Nitrogen Intermediates inMycobacterium tuberculosis: Induction of the 16-Kilodalton α-Crystallin Homolog by Exposure to Nitric Oxide Donors

1999 ◽  
Vol 67 (1) ◽  
pp. 460-465 ◽  
Author(s):  
T. R. Garbe ◽  
N. S. Hibler ◽  
V. Deretic
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Small Heat Shock Protein ◽  
Reactive Nitrogen ◽  
Nitric Oxide Donors ◽  
Specific Response ◽  
Reactive Oxygen Intermediates ◽  
Oxygen Intermediates ◽  
No Donors ◽  
Reactive Nitrogen Intermediates

ABSTRACT In contrast to the apparent paucity of Mycobacterium tuberculosis response to reactive oxygen intermediates, this organism has evolved a specific response to nitric oxide challenge. Exposure of M. tuberculosis to NO donors induces the synthesis of a set of polypeptides that have been collectively termed Nox. In this work, the most prominent Nox polypeptide, Nox16, was identified by immunoblotting and by N-terminal sequencing as the α-crystallin-related, 16-kDa small heat shock protein, sHsp16. A panel of chemically diverse donors of nitric oxide, with the exception of nitroprusside, induced sHsp16 (Nox16). Nitroprusside, a coordination complex of Fe2+ with a nitrosonium (NO+) ion, induced a 19-kDa polypeptide (Nox19) homologous to the nonheme bacterial ferritins. We conclude that the NO response in M. tuberculosis is dominated by increased synthesis of the α-crystallin homolog sHsp16, previously implicated in stationary-phase processes and found in this study to be a majorM. tuberculosis protein induced upon exposure to reactive nitrogen intermediates.

scholarly journals The Contributions of Reactive Oxygen Intermediates and Reactive Nitrogen Intermediates to Listericidal Mechanisms Differ in Macrophages Activated Pre- and Postinfection

1998 ◽  
Vol 66 (9) ◽  
pp. 4043-4049 ◽  
Author(s):  
Satoshi Ohya ◽  
Yoshinari Tanabe ◽  
Masato Makino ◽  
Takamasa Nomura ◽  
Huabao Xiong ◽  
...  
Keyword(s):  
Specific Antigen ◽  
Reactive Oxygen ◽  
Reactive Nitrogen ◽  
Reactive Oxygen Intermediates ◽  
Intracellular Killing ◽  
Spleen Cells ◽  
Oxygen Intermediates ◽  
Normal Spleen ◽  
Reactive Nitrogen Intermediates ◽  
Immune Spleen Cells

ABSTRACT The contribution of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) to the killing of Listeria monocytogenes by macrophages activated by addition of spleen cells from listeria-immune mice plus specific antigen was examined. When macrophages were infected with L. monocytogenes and then spleen cells were added, there was not as big a difference in listericidal activity between macrophages cultured with normal spleen cells and those cultured with immune spleen cells as expected. In this culture system, RNI was mainly involved in the macrophage intracellular killing. In macrophages first activated and then infected, a significant level of enhanced killing was observed. Blockade of ROI production drastically affected the enhanced killing ability, while inhibition of RNI production had a negligible effect. Thus, the contributions of ROI and RNI to listericidal mechanisms of macrophages were different between macrophages activated at pre- and postinfection stages.

scholarly journals Macrophage Microbicidal Mechanisms In Vivo: Reactive Nitrogen versus Oxygen Intermediates in the Killing of Intracellular Visceral Leishmania donovani

1999 ◽  
Vol 189 (4) ◽  
pp. 741-746 ◽  
Author(s):  
Henry W. Murray ◽  
Carl F. Nathan
Keyword(s):  
Respiratory Burst ◽  
Leishmania Donovani ◽  
Early Stage ◽  
Inflammatory Cells ◽  
Reactive Nitrogen ◽  
Oxygen Intermediates ◽  
Reactive Nitrogen Intermediates ◽  
Infected Liver ◽  
Necessary And Sufficient

To determine the relative contributions of respiratory burst–derived reactive oxygen intermediates (ROI) versus reactive nitrogen intermediates (RNI) to macrophage-mediated intracellular host defense, mice genetically deficient in these mechanisms were challenged with Leishmania donovani, a protozoan that selectively parasitizes visceral tissue macrophages. During the early stage of liver infection at wk 2, both respiratory burst–deficient gp91phox−/− (X-linked chronic granulomatous disease [X-CGD]) mice and inducible nitric oxide synthase (iNOS) knockout (KO) mice displayed comparably increased susceptibility. Thereafter, infection was unrestrained in mice lacking iNOS but was fully controlled in X-CGD mice. Mononuclear cell influx into infected liver foci in X-CGD and iNOS KO mice was also overtly impaired at wk 2. However, granuloma assembly in parasitized tissue eventually developed in both hosts but with divergent effects: mature granulomas were functionally active (leishmanicidal) in X-CGD mice but inert in iNOS-deficient animals. These results suggest that (a) ROI and RNI probably act together in the early stage of intracellular infection to regulate both tissue recruitment of mononuclear inflammatory cells and the initial extent of microbial replication, (b) RNI alone are necessary and sufficient for eventual control of visceral infection, and (c) although mature granulomas have traditionally been associated with control of such infections, these structures fail to limit intracellular parasite replication in the absence of iNOS.

scholarly journals Interaction of Antimycobacterial Drugs with the Anti-Mycobacterium avium Complex Effects of Antimicrobial Effectors, Reactive Oxygen Intermediates, Reactive Nitrogen Intermediates, and Free Fatty Acids Produced by Macrophages

2004 ◽  
Vol 48 (6) ◽  
pp. 2132-2139 ◽  
Author(s):  
Keisuke Sano ◽  
Haruaki Tomioka ◽  
Katsumasa Sato ◽  
Chiaki Sano ◽  
Hideyuki Kawauchi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Mycobacterium Avium ◽  
Reactive Oxygen ◽  
Reactive Nitrogen ◽  
Reactive Oxygen Intermediates ◽  
Oxygen Intermediates ◽  
Cell Components ◽  
Reactive Nitrogen Intermediates ◽  
Important Possibility

ABSTRACT The profiles of the interaction of antimycobacterial drugs with macrophage (MΦ) antimicrobial mechanisms have yet to be elucidated in detail. We examined the effects of various antimycobacterial drugs on the anti-Mycobacterium avium complex (MAC) antimicrobial activity of reactive oxygen intermediates (ROIs), especially of an H2O2-halogen (H2O2-Fe2+-NaI)-mediated bactericidal system, reactive nitrogen intermediates (RNIs), and free fatty acids (FFAs), which are known as central antimicrobial effectors of host MΦs against mycobacterial pathogens. We have found that certain drugs, such as rifampin (RIF), rifabutin (RFB), isoniazid (INH), clofazimine (CLO), and some fluoroquinolones, strongly or moderately reduced the anti-MAC activity of the H2O2-Fe2+-NaI system, primarily by inhibiting the generation of hypohalite ions and in part by interfering with the halogenation reaction of bacterial cell components due to the H2O2-Fe2+-NaI system. This phenomenon is specific to the H2O2-Fe2+-NaI system, since these drugs did not reduce the anti-MAC activity of RNIs and FFAs. From the perspective of the chemotherapy of MAC infections, the present findings indicate an important possibility that certain antimycobacterial drugs, such as rifamycins (RIF and RFB), INH, CLO, and also some types of fluoroquinolones, may interfere with the ROI-mediated antimicrobial mechanisms of host MΦs against intracellular MAC organisms.

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