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,§
*
Departments of Molecular Genetics and Biochemistry, and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and Departments of
Pathology,
Medicine, and
§
Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10467
A unique feature of Mycobacterium tuberculosis is its
ability to establish latent infection in the human host, which can
reactivate to cause disease years later. In the present study, the
mechanisms involved in the control of latent tuberculous infection were
examined using two murine experimental tuberculosis models. Analysis of
the model involving infection of mice with a relatively low inoculum of
the virulent Erdman strain of M. tuberculosis indicated
that in vivo inhibition of reactive nitrogen intermediate (RNI)
production by the nitric oxide synthase inhibitor aminoguanidine
resulted in reactivation. This reactivation was evidenced by
hepatosplenomegaly, a robust tissue granulomatous reaction, and
increased bacillary load. IFN-
, TNF-
, and inducible nitric oxide
synthase were all expressed throughout the latent phase of infection.
Reactivation of latent tuberculous infection by aminoguanidine
treatment was confirmed using a second murine tuberculosis model based
on treatment with antimycobacterial drugs. Results obtained using this
drug-based model also suggested the existence of an RNI-independent
antimycobacterial mechanism(s) operative in the latent phase of
infection. Together, these data suggest that both RNI-dependent and
-independent mechanisms contribute to the prevention of tuberculous
reactivation.
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D. R. Sherman, M. Voskuil, D. Schnappinger, R. Liao, M. I. Harrell, and G. K. Schoolnik Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha -crystallin PNAS, June 19, 2001; 98(13): 7534 - 7539. [Abstract] [Full Text] [PDF]
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V. P. Mohan, C. A. Scanga, K. Yu, H. M. Scott, K. E. Tanaka, E. Tsang, M. C. Tsai, J. L. Flynn, and J. Chan Effects of Tumor Necrosis Factor Alpha on Host Immune Response in Chronic Persistent Tuberculosis: Possible Role for Limiting Pathology Infect. Immun., March 1, 2001; 69(3): 1847 - 1855. [Abstract] [Full Text] [PDF]
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T. Mogues, M. E. Goodrich, L. Ryan, R. LaCourse, and R. J. North The Relative Importance of T Cell Subsets in Immunity and Immunopathology of Airborne Mycobacterium tuberculosis Infection in Mice J. Exp. Med., February 5, 2001; 193(3): 271 - 280. [Abstract] [Full Text] [PDF]
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L. B. Adams, C. K. Job, and J. L. Krahenbuhl Role of Inducible Nitric Oxide Synthase in Resistance to Mycobacterium leprae in Mice Infect. Immun., September 1, 2000; 68(9): 5462 - 5465. [Abstract] [Full Text] [PDF]
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C. A. Scanga, V.P. Mohan, K. Yu, H. Joseph, K. Tanaka, J. Chan, and J. L. Flynn Depletion of Cd4+ T Cells Causes Reactivation of Murine Persistent Tuberculosis despite Continued Expression of Interferon {gamma} and Nitric Oxide Synthase 2 J. Exp. Med., August 7, 2000; 192(3): 347 - 358. [Abstract] [Full Text] [PDF]
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C. Nathan and M. U. Shiloh Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens PNAS, August 1, 2000; 97(16): 8841 - 8848. [Abstract] [Full Text] [PDF]
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L. R. Brunet, M. Beall, D. W. Dunne, and E. J. Pearce Nitric Oxide and the Th2 Response Combine to Prevent Severe Hepatic Damage During Schistosoma mansoni Infection J. Immunol., November 1, 1999; 163(9): 4976 - 4984. [Abstract] [Full Text] [PDF]
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C. A. Scanga, V. P. Mohan, H. Joseph, K. Yu, J. Chan, and J. L. Flynn Reactivation of Latent Tuberculosis: Variations on the Cornell Murine Model Infect. Immun., September 1, 1999; 67(9): 4531 - 4538. [Abstract] [Full Text] [PDF]
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C. Sciorati, P. Rovere, M. Ferrarini, C. Paolucci, S. Heltai, R. Vaiani, E. Clementi, and A. A. Manfredi Generation of Nitric Oxide by the Inducible Nitric Oxide Synthase Protects {gamma}{delta} T Cells from Mycobacterium tuberculosis-Induced Apoptosis J. Immunol., August 1, 1999; 163(3): 1570 - 1576. [Abstract] [Full Text] [PDF]
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A. M. Caruso, N. Serbina, E. Klein, K. Triebold, B. R. Bloom, and J. L. Flynn Mice Deficient in CD4 T Cells Have Only Transiently Diminished Levels of IFN-{gamma}, Yet Succumb to Tuberculosis J. Immunol., May 1, 1999; 162(9): 5407 - 5416. [Abstract] [Full Text] [PDF]
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A. G. D. Bean, D. R. Roach, H. Briscoe, M. P. France, H. Korner, J. D. Sedgwick, and W. J. Britton Structural Deficiencies in Granuloma Formation in TNF Gene-Targeted Mice Underlie the Heightened Susceptibility to Aerosol Mycobacterium tuberculosis Infection, Which Is Not Compensated for by Lymphotoxin J. Immunol., March 15, 1999; 162(6): 3504 - 3511. [Abstract] [Full Text] [PDF]
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D. Schluter, M. Deckert-Schluter, E. Lorenz, T. Meyer, M. Rollinghoff, and C. Bogdan Inhibition of Inducible Nitric Oxide Synthase Exacerbates Chronic Cerebral Toxoplasmosis in Toxoplasma gondii-Susceptible C57BL/6 Mice But Does Not Reactivate the Latent Disease in T. gondii-Resistant BALB/c Mice J. Immunol., March 15, 1999; 162(6): 3512 - 3518. [Abstract] [Full Text] [PDF]
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A. S. MacFarlane, M. G. Schwacha, and T. K. Eisenstein In Vivo Blockage of Nitric Oxide with Aminoguanidine Inhibits Immunosuppression Induced by an Attenuated Strain of Salmonella typhimurium, Potentiates Salmonella Infection, and Inhibits Macrophage and Polymorphonuclear Leukocyte Influx into the Spleen Infect. Immun., February 1, 1999; 67(2): 891 - 898. [Abstract] [Full Text] [PDF]
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