Susceptibility of a panel of virulent strains of Mycobacterium tuberculosis to 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.

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

Journal of Experimental Medicine ◽

10.1084/jem.175.4.1111 ◽

1992 ◽

Vol 175 (4) ◽

pp. 1111-1122 ◽

Cited By ~ 671

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.

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Surfactant protein A suppresses reactive nitrogen intermediates by alveolar macrophages in response to Mycobacterium tuberculosis

Journal of Clinical Investigation ◽

10.1172/jci2991 ◽

1999 ◽

Vol 103 (4) ◽

pp. 483-490 ◽

Cited By ~ 51

Author(s):

Rajamouli Pasula ◽

Jo Rae Wright ◽

Diane L. Kachel ◽

William J. Martin

Keyword(s):

Mycobacterium Tuberculosis ◽

Alveolar Macrophages ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Reactive Nitrogen ◽

Reactive Nitrogen Intermediates

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Peptide methionine sulfoxide reductase from Escherichia coli and Mycobacterium tuberculosis protects bacteria against oxidative damage from reactive nitrogen intermediates

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.161295398 ◽

2001 ◽

Vol 98 (17) ◽

pp. 9901-9906 ◽

Cited By ~ 150

Author(s):

G. S. John ◽

N. Brot ◽

J. Ruan ◽

H. Erdjument-Bromage ◽

P. Tempst ◽

...

Keyword(s):

Escherichia Coli ◽

Mycobacterium Tuberculosis ◽

Oxidative Damage ◽

Methionine Sulfoxide ◽

Methionine Sulfoxide Reductase ◽

Reactive Nitrogen ◽

Reactive Nitrogen Intermediates ◽

Peptide Methionine Sulfoxide Reductase

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Comparative roles of free fatty acids with reactive nitrogen intermediates and reactive oxygen intermediates in expression of the anti-microbial activity of macrophages against Mycobacterium tuberculosis

Clinical & Experimental Immunology ◽

10.1046/j.1365-2249.2000.01298.x ◽

2000 ◽

Vol 121 (2) ◽

pp. 302-310 ◽

Cited By ~ 43

Author(s):

T. Akaki ◽

H. Tomioka ◽

T. Shimizu ◽

S. Dekio ◽

K. Sato

Keyword(s):

Fatty Acids ◽

Mycobacterium Tuberculosis ◽

Free Fatty Acids ◽

Microbial Activity ◽

Reactive Oxygen ◽

Reactive Nitrogen ◽

Reactive Oxygen Intermediates ◽

Oxygen Intermediates ◽

Reactive Nitrogen Intermediates

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ALKYL HYDROPEROXIDE REDUCTASE SUBUNIT C (AHPC) FROM MYCOBACTERIUM TUBERCULOSIS PROTECTS MAMMALIAN CELLS AGAINST REACTIVE NITROGEN INTERMEDIATES

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)41758-7 ◽

1997 ◽

Vol 75 ◽

pp. 91

Author(s):

L. Chen ◽

Q.-W. Xie ◽

C.F. Nathan

Keyword(s):

Mycobacterium Tuberculosis ◽

Mammalian Cells ◽

Reactive Nitrogen ◽

Alkyl Hydroperoxide Reductase ◽

Subunit C ◽

Alkyl Hydroperoxide ◽

Reactive Nitrogen Intermediates

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

Infection and Immunity ◽

10.1128/iai.67.1.460-465.1999 ◽

1999 ◽

Vol 67 (1) ◽

pp. 460-465 ◽

Cited By ~ 63

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.

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