Download PDF
Semin Respir Crit Care Med 2004; 25(1): 53-61
DOI: 10.1055/s-2004-822305
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Immunity Against Mycobacteria

Carol M. Mason1 , Juzar Ali1
  • 1Division of Pulmonary/Critical Care Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana
Further Information

Publication History

Publication Date:
12 March 2004 (online)

    Permissions and Reprints

Mycobacterium tuberculosis is the most prevalent infectious pathogen in the world, largely due to its unique interactions with the human immune system. Even in a normal host, a frequent outcome of infection with M. tuberculosis is failure to completely eradicate the organisms, despite the development of cell-mediated immunity. Viable organisms persist in a state in which they do not progressively replicate, leading to latent infection, which carries a risk of breakdown into active (reactivation) tuberculosis at some point later in life. Key features of the immune response against mycobacteria are reviewed here, and potential mechanisms by which the organisms may subvert these host defenses are discussed. Despite the multicellular nature of the host response to infecting mycobacteria, the organisms cannot be eradicated and contribute to the ongoing worldwide epidemic with tuberculosis.

KEYWORDS

Mycobacteria - immunity - cytokines - granuloma

REFERENCES

  • 1 World Health Organization .Groups at risk: report on the tuberculosis epidemic. Geneva; WHO 1996
    Google Scholar
  • 2 Raviglione M, Snider Jr D, Kochi A. Global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic.  JAMA. 1995;  273 220-226
    CrossrefPubMedGoogle Scholar
  • 3 Sahn S, Neff T. Miliary tuberculosis.  Am J Med. 1974;  56 495-505
    CrossrefPubMedGoogle Scholar
  • 4 Barnes P, Bloch A, Davidson P, Snider D. Tuberculosis in patients with human immunodeficiency virus infection.  N Engl J Med. 1991;  324 1644-1650
    PubMedGoogle Scholar
  • 5 Cohn D, O'Brien R, Geiter L et al.. American Thoracic Society/Centers for Disease Control and Prevention: targeted tuberculin testing and treatment of latent tuberculosis infection.  Am J Respir Crit Care Med. 2000;  161 S221-S247
    PubMedGoogle Scholar
  • 6 Reiling N, Holscher C, Fehrenbach A et al.. Cutting edge: toll-like receptor (TLR)2- and TLR4-mediated pathogen recognition in resistance in airborne infection with Mycobacterium tuberculosis .  J Immunol. 2002;  169 3480-3484
    PubMedGoogle Scholar
  • 7 Schlesinger L. Role of mononuclear phagocytes in M. tuberculosis pathogenesis.  J Investig Med. 1996;  44 312-323
    PubMedGoogle Scholar
  • 8 Sturgill-Koszcki S, Schlesinger P, Chakraborty P et al.. Lack of acidification in mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase.  Science. 1994;  263 678-681
    PubMedGoogle Scholar
  • 9 Malik Z, Thompson C, Hashimi S, Porter B, Iyer S, Kusner D. Cutting edge: Mycobacterium tuberculosis blocks Ca2+ signaling and phagosome maturation in human macrophages via specific inhibition of sphingosine kinase.  J Immunol. 2003;  170 2811-2815
    PubMedGoogle Scholar
  • 10 Russell D. Mycobacterium tuberculosis: here today and here tomorrow.  Nature Reviews. 2001;  2 1-9
    PubMedGoogle Scholar
  • 11 Brown D, Miles B, Zwilling B. Growth of Mycobacterium tuberculosis in BCG-resistant and -susceptible mice: establishment of latency and reactivation.  Infect Immun. 1995;  63 2243-2247
    PubMedGoogle Scholar
  • 12 Bellamy R, Ruwende C, Corrah T, McAdam K, Whittle H, Hill A. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.  N Engl J Med. 1998;  338 640-644
    CrossrefPubMedGoogle Scholar
  • 13 Schaible U, Sturgill-Koszycki S, Schlesinger P, Russell D. Cytokine activation leads to acidification and increases maturation of Mycobacterium avium-containing phagosomes in murine macrophages.  J Immunol. 1998;  160 1290-1296
    PubMedGoogle Scholar
  • 14 Denis M. Interferon-gamma-treated macrophages inhibit growth of tubercle bacilli via the generation of reactive nitrogen intermediates.  Cell Immunol. 1991;  132 150-157
    CrossrefPubMedGoogle Scholar
  • 15 Flesch I, Kaufmann S. Mechanisms involved in mycobacterial growth inhibition by gamma interferon-activated bone marrow macrophages: role of reactive nitrogen intermediates.  Infect Immun. 1991;  59 3213-3218
    PubMedGoogle Scholar
  • 16 Wang J, Wakeham J, Harkness R, Xing Z. Macrophages are a significant source of type 1 cytokines during mycobacterial infection.  J Clin Invest. 1999;  103 1023-1029
    PubMedGoogle Scholar
  • 17 Park A, Hondowicz B, Kopf M, Scott P. The role of IL-12 in maintaining resistance to Leishmania major .  J Immunol. 2002;  168 5771-5777
    CrossrefPubMedGoogle Scholar
  • 18 Fulton S, Johnsen J, Wolf S, Sieburth D, Boom W. Interleukin-12 production by human monocytes infected with Mycobacterium tuberculosis: role of phagocytosis.  Infect Immun. 1996;  64 2523-2531
    PubMedGoogle Scholar
  • 19 Flesch I, Hess J, Huang S et al.. Early interleukin 12 production by macrophages in response to mycobacteial infection depends on interferon-γ and tumor necrosis factor-α.  J Exp Med. 1995;  181 1615-1621
    CrossrefPubMedGoogle Scholar
  • 20 Flynn J, Goldstein M, Triebold K, Sypek J, Wolf S, Bloom B. IL-12 increases resistance of BALB/c mice to Mycobacterium tuberculosis infection.  J Immunol. 1995;  155 2515-2524
    PubMedGoogle Scholar
  • 21 Cooper A, Magram J, Ferrante J, Orme I. Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis .  J Exp Med. 1997;  186 39-45
    CrossrefPubMedGoogle Scholar
  • 22 Cooper A, Kipnis A, Turner J, Magram J, Ferrante J, Orme I. Mice lacking bioactive IL-12 can generate protective antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present.  J Immunol. 2002;  168 1322-1327
    PubMedGoogle Scholar
  • 23 Yamada H, Mizumo S, Horai R, Iwakura Y, Sugawara I. Protective role of interleukin-1 in mycobacterial infection in IL-1 α/β double-knockout mice.  Lab Invest. 2000;  80 759-767
    PubMedGoogle Scholar
  • 24 Adams L, Mason C, Kolls J, Scollard D, Krahenbuhl J, Nelson S. Exacerbation of acute and chronic murine tuberculosis by administration of tumor necrosis factor receptor-expressing adenovirus.  J Infect Dis. 1995;  171 400-405
    PubMedGoogle Scholar
  • 25 Kindler V, Sappino A, Grau G, Piguet P, Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection.  Cell. 1989;  56 731-740
    CrossrefPubMedGoogle Scholar
  • 26 Flynn J, Goldstein M, Chan J et al.. Tumor necrosis factor-α is required in the protective immune response against Mycobacterium tuberculosis in mice.  Immunity. 1995;  2 561-572
    CrossrefPubMedGoogle Scholar
  • 27 Keane J, Gershon S, Wise R et al.. Tuberculosis associated with infliximab, a tumor necrosis factor (alpha)-neutralizing agent.  N Engl J Med. 2001;  345 1098-1104
    CrossrefPubMedGoogle Scholar
  • 28 Kremer L, Dupre L, Wolowczuk I, Locht C. In vivo immunomodulation following intradermal injection with DNA encoding IL-18.  J Immunol. 1999;  163 3226-3231
    PubMedGoogle Scholar
  • 29 Yamada G, Shijubo N, Shigehara K, Okamura H, Kurimoto M, Abe S. Increased levels of circulating interleukin-18 in patients with advanced tuberculosis.  Am J Respir Crit Care Med. 2000;  161 1786-1789
    PubMedGoogle Scholar
  • 30 Sugawara I, Yamada H, Kaneko H, Mizuno S, Takeda K, Akira S. Role of interleukin-18 (IL-18) in mycobacterial infection in IL-18-gene-disrupted mice.  Infect Immun. 1999;  67 2585-2589
    PubMedGoogle Scholar
  • 31 Orme I, Roberts A, Griffin J, Abrams J. Cytokine secretion by CD4 T lymphocytes acquired in response to Mycobacterium tuberculosis infection.  J Immunol. 1993;  151 518-525
    PubMedGoogle Scholar
  • 32 Gong J, Zhang M, Modlin R et al.. Interleukin-10 downregulates Mycobacterium tuberculosis-induced Th1 responses and CTLA-4 expression.  Infect Immun. 1996;  64 913-918
    PubMedGoogle Scholar
  • 33 Murray P, Wang L, Onufryk C, Tepper R, Young R. T cell-derived IL-10 antagonizes macrophage function in mycobacterial infection.  J Immunol. 1997;  158 315-321
    PubMedGoogle Scholar
  • 34 Murray P, Young R. Increased antimycobacterial immunity in interleukin-10-deficient mice.  Infect Immun. 1999;  67 3087-3095
    PubMedGoogle Scholar
  • 35 Boussiotis V, Tsai E, Yunis E et al.. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients.  J Clin Invest. 2000;  105 1317-1325
    PubMedGoogle Scholar
  • 36 Sugawara I, Yamada H, Mizuno S, Iwakura Y. IL-4 is required for defense against mycobacterial infection.  Microbiol Immunol. 2000;  44 971-979
    PubMedGoogle Scholar
  • 37 Adams L, Fukutomi Y, Krahenbuhl J. Regulation of murine macrophage effector functions by lipoarabinomannan from mycobacterial strains with different degrees of virulence.  Infect Immun. 1993;  61 4173-4181
    PubMedGoogle Scholar
  • 38 Luster A. Chemokines: chemotactic cytokines that mediate inflammation.  N Engl J Med. 1998;  338 436-445
    CrossrefPubMedGoogle Scholar
  • 39 Sauty A, Dziejman M, Taha R et al.. The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells.  J Immunol. 1999;  162 3549-3558
    PubMedGoogle Scholar
  • 40 Sadek M, Sada E, Toossi Z, Schwander S, Rich E. Chemokines induced by infection of mononuclear phagocytes with mycobacteria and present in lung alveoli during active pulmonary tuberculosis.  Am J Respir Cell Mol Biol. 1998;  19 513-521
    PubMedGoogle Scholar
  • 41 Saukkonen J, Bazydlo B, Thomas M, Streiter R, Keane J, Kornfeld H. β-chemokines are induced by Mycobacterium tuberculosis and inhibit its growth.  Infect Immun. 2002;  70 1684-1693
    CrossrefPubMedGoogle Scholar
  • 42 Qiu B, Frait K, Reich F, Komuniecki E, Chensue S. Chemokine expression dynamics in mycobacterial (type-1) and schistosomal (type-2) antigen-elicited pulmonary granuloma formation.  Am J Pathol. 2001;  158 1503-1515
    PubMedGoogle Scholar
  • 43 Rhoades E, Cooper A, Orme I. Chemokine response in mice infected with Mycobacterium tuberculosis .  Infect Immun. 1995;  63 3871-3877
    PubMedGoogle Scholar
  • 44 Lin Y, Zhang M, Barnes P. Chemokine production by a human alveolar epithelial cell line in response to Mycobacterium tuberculosis .  Infect Immun. 1998;  66 1121-1126
    PubMedGoogle Scholar
  • 45 Muller I, Cobbold S, Waldmann H, Kaufmann S. Impaired resistance to Mycobacterium tuberculosis infection after selective in vivo depletion of L3T4+ and Lyt-2+ T cells.  Infect Immun. 1987;  55 2037-2041
    PubMedGoogle Scholar
  • 46 Scanga C, Mohan V, Yu K et al.. Depletion of CD4+ T cells causes reactivation of murine persistent tuberculosis despite continued expression of interferon γ and nitric oxide synthase 2.  J Exp Med. 2000;  192 347-358
    CrossrefPubMedGoogle Scholar
  • 47 Saunders B, Frank A, Orme I, Cooper A. CD4 is required for the development of a protective granulomatous response to pulmonary tuberculosis.  Cell Immunol. 2002;  216 65-72
    CrossrefPubMedGoogle Scholar
  • 48 Graham N, Chaisson R. Tuberculosis and HIV infection: epidemiology, pathogenesis, and clinical aspects.  Ann Allergy. 1993;  71 421-428
    PubMedGoogle Scholar
  • 49 Cooper A, Dalton D, Stewart T, Griffin J, Russell D, Orme I. Disseminated tuberculosis in interferon γ gene-disrupted mice.  J Exp Med. 1993;  178 2243-2247
    CrossrefPubMedGoogle Scholar
  • 50 Flynn J, Chan J, Triebold K, Dalton D, Stewart T, Bloom B. An essential role for interferon γ in resistance to Mycobacterium tuberculosis infection.  J Exp Med. 1993;  178 2249-2254
    CrossrefPubMedGoogle Scholar
  • 51 Jouanguy E, Altare F, Lamhamedi S et al.. Interferon-γ-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection.  N Engl J Med. 1996;  335 1956-1961
    CrossrefPubMedGoogle Scholar
  • 52 Ottenhoff T, Kumararatne D, Casanova J. Novel human immunodeficiencies reveal the essential role of type-1 cytokines in immunity to intracellular bacteria.  Immunol Today. 1998;  19 491-494
    CrossrefPubMedGoogle Scholar
  • 53 Lopez-Maderuelo D, Arnalich F, Serantes R et al.. Interferon-γ and interleukin-10 gene polymorphisms in pulmonary tuberculosis.  Am J Respir Crit Care Med. 2003;  167 970-975
    CrossrefPubMedGoogle Scholar
  • 54 Giosue S, Casarini M, Alemanno L et al.. Effects of aerosolized interferon-α in patients with pulmonary tuberculosis.  Am J Respir Crit Care Med. 1998;  158 1156-1162
    PubMedGoogle Scholar
  • 55 Condos R, Rom W, Schluger N. Treatment of multidrug-resistant pulmonary tuberculosis with interferon-γ via aerosol.  Lancet. 1997;  349 1513-1515
    CrossrefPubMedGoogle Scholar
  • 56 Zea A, Ochoa M, Ghosh P et al.. Changes in expression of signal transduction proteins in T lymphocytes of patients with leprosy.  Infect Immun. 1998;  66 499-504
    PubMedGoogle Scholar
  • 57 Zea A, Culotta K, Ali J et al.. Alterations in T cell signal transduction proteins in patients with tuberculosis.  FASEB J. 2002;  16 A300
    PubMedGoogle Scholar
  • 58 Serbina N, Flynn J. Early emergence of CD8+ T cells primed for the production of type 1 cytokines in the lungs of Mycobacterium tuberculosis-infected mice.  Infect Immun. 1999;  67 3980-3988
    PubMedGoogle Scholar
  • 59 Cooper A, D'Souza C, Frank A, Orme I. The course of Mycobacterium tuberculosis infection in the lungs of mice lacking expression of either perforin- or granzyme-mediated cytolytic mechanisms.  Infect Immun. 1997;  65 1317-1320
    PubMedGoogle Scholar
  • 60 Serbina N, Liu C, Scanga C, Flynn J. CD8+ CTL from lungs of Mycobacterium tuberculosis-infected mice express perforin in vivo and lyse infected macrophages.  J Immunol. 2000;  165 353-363
    PubMedGoogle Scholar
  • 61 Pinxteren L V, Cassidy J, Smedegaard B, Agger E, Andersen P. Control of latent Mycobacterium tuberculosis infection is dependent on CD8 T cells.  Eur J Immunol. 2000;  30 3689-3698
    CrossrefPubMedGoogle Scholar
  • 62 Vordermeier H, Venkataprasad N, Harris D, Ivanyi J. Increase in tuberculous infection in the organs of B cell-deficient mice.  Clin Exp Immunol. 1996;  106 312-316
    CrossrefPubMedGoogle Scholar
  • 63 Kaufmann S. γ/δ and other unconventional T lymphocytes: what do they see and what do they do?.  Proc Natl Acad Sci USA. 1996;  93 2272-2279
    CrossrefPubMedGoogle Scholar
  • 64 D'Souza C, Cooper A, Frank A, Mazzaccaro R, Bloom B, Orme I. An anti-inflammatory role for γδ T lymphocytes in acquired immunity to Mycobacterium tuberculosis .  J Immunol. 1997;  158 1217-1221
    PubMedGoogle Scholar
  • 65 Gonzalez-Juarrero M, Turner O, Turner J, Marietta P, Brooks J, Orme I. Temporal and spatial arrangement of lymphocytes within lung granulomas induced by aerosol infection with Mycobacterium tuberculosis .  Infect Immun. 2001;  69 1722-1728
    CrossrefPubMedGoogle Scholar
  • 66 Teitelbaum R, Glatman-Freedman A, Chen B et al.. A mAb recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival.  Proc Natl Acad Sci USA. 1998;  95 15688-15693
    CrossrefPubMedGoogle Scholar

Carol M MasonM.D. 

Division of Pulmonary/Critical Care Medicine, Louisiana State University Health Sciences Center

1901 Perdido St., Ste. 3205

New Orleans, LA 70112-1393

Email: mason@lsuhsc.edu