Inflammation pp 153-166 | Cite as

Mechanisms of Mycobacterium Avium Pathogenesis

  • Luiz E. Bermudez
  • Dirk Wagner
  • Danuta Sosnowska


Infections caused by Mycobacterium avium are common in AIDS patients and patients with chronic lung diseases. The bacterium can be acquired both through the intestinal route and respiratory route. M. avium is capable of invading mucosal epithelial cells and translocating across the mucosa. The bacterium can infect macrophages, interfering with several functions of the host cell. The host defense against M. avium is primarily dependent on CD4+ T lymphocytes and natural killer cells. Activated macrophages can inhibit or kill intracellular bacteria by mechanisms that are currently unknown, but M. avium can invade resting macrophages and suppress key aspects of their function by triggering the release of transforming growth factor β and interleukin 10. Co-infection with HIV-1 appears to be mutually beneficial, with both organisms growing faster.

Key words

M. avium pathogenesis. 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abel L., Sanchez E. O., Oberti J., Thuc N. V., Hoa L. V., Lap V. D., Skamene E., Lagrange P. H. and Schurr E. (1998): Susceptibility to leprosy is linked to the human NRAMP1 gene. J. Infect. Dis., 177, 133–145.PubMedCrossRefGoogle Scholar
  2. Agranoff D., Monahan I. M., Mangan J. A., Butcher P. D. and Krishna S. (1999): Mycobacterium tuberculosis expresses a novel pH-dependent divalent cation transporter belonging to the Nramp family. J. Exp. Med., 190, 717–724.Google Scholar
  3. Aitken M. L., Burke W., McDonald G., Wallis C., Ramsey B. and Nolan C. (1993): Nontuberculous mycobacterial disease in adult cystic fibrosis patients. Chest, 103, 1096–1099.PubMedCrossRefGoogle Scholar
  4. Altare F., Durandy A., Lammas D., Emile J. E, Lamhamedi S., Le Deist E, Drysdale R, Jouanguy E., Doffinger R., Bernaudin E, Jeppsson O., Gollob J. A., Meinl E., Segal A. W., Fischer A., Kumararatne D. and Casanova J. L. (1998): Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science, 280, 1432–1435.PubMedCrossRefGoogle Scholar
  5. Appelberg R., Castro A. G., Pedrosa J., Silva R. A., Orme I. M. and Minoprio P. (1994): Role of gamma interferon and tumor necrosis factor alpha during T-cell-independent and dependent phases of Mycobacterium avium infection. Infect. Immun., 62, 3962–3971.PubMedGoogle Scholar
  6. Barker L. P., George K. M., Falkow S. and Small P. L. (1997): Differential trafficking of live and dead Mycobacterium marinum organisms in macrophages. Infect. Immun., 65, 1497–1504.PubMedGoogle Scholar
  7. Barton C. H., Biggs T. E., Baker S. T., Bowen H. and Atkinson P. G. (1999): Nrampl: a link between intracellular iron transport and innate resistance to intracellular pathogens. J. Leukoc. Biol., 66, 757–762.PubMedGoogle Scholar
  8. Bellamy R., Ruwende C., Corrah T., McAdam K. P., Whittle H. C. and Hill A. V. (1998): Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N. Engl. J. Med., 338, 640–644.PubMedCrossRefGoogle Scholar
  9. Bentrup K. H. Z., Miczak A., Swenson D. L. and Russell D. G. (1999): Characterization of activity and expression of isocitrate lyase in Mycobacterium avium and Mycobacterium tuberculosis. J. Bacteriol., 181, 7161–7167.Google Scholar
  10. Bermudez L. E. (1993a): Differential mechanisms of intracellular killing of Mycobacterium avium and Listeria monocytogenes by activated human and murine macrophages. The role of nitric oxide. Clin. Exp. Immunol., 91, 277.Google Scholar
  11. Bermudez L. E. (1993b): Production of transforming growth factor ß by Mycobacterium avium infected macrophages is associated with unresponsiveness to interferon-gamma. J. Immunol., 150, 1838–1843.PubMedGoogle Scholar
  12. Bermudez L. E. and Champsi J. (1993): Infection with M. avium induces production of IL-10 and administration of IL-10 antibody is associated with enhanced resistance to infection in mice. Infect. Immun., 61, 3093–3096.PubMedGoogle Scholar
  13. Bermudez L. E. and Goodman J. (1996): Mycobacterium tuberculosis invades and replicates within type II alveolar cells. Infect. Immun., 64, 1400–1406.Google Scholar
  14. Bermudez L. E., Goodman J. and Petrofsky M. (1999): Role of complement receptors in uptake of Mycobacterium avium by macrophages in vivo: evidence from studies using CD18-deficient mice. Infect. Immun., 67, 4912–4916.PubMedGoogle Scholar
  15. Bermudez L. E., Kolonoski P. and Young L. S. (1990): Natural killer cell activity and macrophage dependent inhibition of growth or killing of Mycobacterium avium complex in a mouse model. J. Leukoc. Biol., 47, 135–142.PubMedGoogle Scholar
  16. Bermudez L. E., Martinelli J., Petrofsky M., Kolonoski P. and Young L. S. (1994): Recombinant granulocyte-macrophage colony stimulating factor enhances the effects of antibiotics against M. avium complex. J. Infect. Dis., 169, 575–580.PubMedCrossRefGoogle Scholar
  17. Bermudez L. E., Parker A. and Goodman J. R. (1997a): Growth within macrophages increas-Google Scholar
  18. es the efficiency of Mycobacterium avium in invading other macrophages by a complement receptor-independent pathway. Infect. Immun., 65, 1916–1925.Google Scholar
  19. Bermudez L. E. and Petrofsky M. (1999): Host defense against Mycobacterium avium does not have an absolute requirement for major histocompatibility complex class I-restricted T cells. Infect. Immun., 67, 3108–3111.PubMedGoogle Scholar
  20. Bermudez L. E., Petrofsky M. and Goodman J. (1997b): Exposure to low oxygen tension and increased osmolarity enhance the ability of Mycobacterium avium to enter intestinal epithelial (HT-29) cells. Infect. Immun., 65, 3768–3773.PubMedGoogle Scholar
  21. Bermudez L. E., Petrofsky M., Kolonoski P. and Young L. S. (1992): An animal model of Mycobacterium avium complex disseminated infection after colonization of the intestinal tract. J. Infect. Dis., 165, 75–79.PubMedCrossRefGoogle Scholar
  22. Bermudez L. E., Petrofsky M., Wu M. and Young L. S. (1998a): Clarithromycin significantly improves interleukin-12-mediated anti-Mycobacterium avium activity and abolishes toxicity in mice. J. Infect. Dis., 178, 896–899.PubMedCrossRefGoogle Scholar
  23. Bermudez L. E., Sangari E. J., Petrofsky M. and Goodman J. (1998b): Mycobacterium avium invasion. In Molecular signals and infectious diseases. Institut Pasteur Centre of Information Scientifique, 17–26.Google Scholar
  24. Bermudez L. E., Shelton K. and Young L. S. (1995): Comparison of the ability of M. avium, M. smegmatis, and M. tuberculosis to invade and replicate within HEp-2 epithelial cells. Tuber. Lung Dis., 76, 240–247.PubMedCrossRefGoogle Scholar
  25. Bermudez L. E., Stevens P., Kolonoski P., Wu M. and Young L. S. (1989): Treatment of disseminated Mycobacterium avium complex infection in mice with recombinant interleukin-2 and tumor necrosis factor. J. Immunol., 143, 2996–3002.PubMedGoogle Scholar
  26. Bermudez L. E. and Young L. S. (1988): Tumor necrosis factor, alone or in combination with IL-2, but not IFN-gamma, is associated with macrophage killing of Mycobacterium avium complex. J. Immunol., 9, 3006–3013.Google Scholar
  27. Bermudez L. E. and Young L. S. (1989): Oxidative and non-oxidative intracellular killing of Mycobacterium avium complex. Microb. Pathog., 7, 289–297.PubMedCrossRefGoogle Scholar
  28. Bermudez L. E. and Young L. S. (1990): Recombinant granulocyte-macrophage colony stimulating factor activates human macrophages to inhibit growth or kill Mycobacterium avium complex. J. Leukoc. Biol., 48, 67–73.PubMedGoogle Scholar
  29. Bermudez L. E. and Young L. S. (1991): Natural killer cell dependent mycobacteriostatic and mycobactericidal activity in human macrophages. J. Immunol., 146, 265–269.PubMedGoogle Scholar
  30. Bermudez L. E. and Young L. S. (1994): Factors affecting invasion of HT-29 and HEp-2 epithelial cells by organisms of the Mycobacterium avium complex. Infect. Immun., 62, 2021–2026.PubMedGoogle Scholar
  31. Bermudez L. E., Young L. S. and Enkel H. (1991): Interaction of Mycobacterium avium complex with human macrophages: roles of membrane receptors and serum proteins. Infect. Immun., 59, 1697–1702.PubMedGoogle Scholar
  32. Blanchard D. K., Michelini-Norris M. B., Pearson C. A., Freitag C. S. and Djeu J. Y. (1991): Mycobacterium avium-intracellulare induces interleukin-6 from human monocytes and large granular lymphocytes. Blood, 77, 2218–2224.Google Scholar
  33. Bodmer T., Miltner E. and Bermudez L. E. (2000): Mycobacterium avium resists exposure to the acidic conditions of the stomach. FEMS Microbiol. Lett., 182, 45–49.Google Scholar
  34. Castro A. G., Silva R. A. and Appelberg R. (1995): Endogenously produced IL-12 is required for the induction of protective T cells during Mycobacterium avium infections in mice. J. Immunol., 155, 2013–2019.PubMedGoogle Scholar
  35. Clemens D. L. and Horwitz M. A. (1995): Characterization of the Mycobacterium tuberculosis phagosome and evidence that phagosomal maturation is inhibited. J. Exp. Med., 181, 257–270.PubMedCrossRefGoogle Scholar
  36. Curtis K. J. and Sleisenger M. H. (1978): Infections and parasitic diseases. In Sleisenger M. H. and Fordham J. S. (eds.): Gastrointestinal diseases. Saunders, Philadelphia.Google Scholar
  37. Damsker B. and Bottone E. J. (1985): Mycobacterium avium-Mycobacterium intracellulare from the intestinal tracts of patients with the acquired immunodeficiency syndrome: concepts regarding acquisition and pathogenesis. J. Infect. Dis., 151, 179–181.Google Scholar
  38. De Chastellier C. and Lang T. (1995): Phagocytic processing of the macrophages endoparasite Mycobacterium avium in comparison which contain Bacillus subtilus or latex beads. Eur. J. Cell Biol., 68, 167–182.PubMedGoogle Scholar
  39. Denis M. (1991): Tumor necrosis factor and granulocyte macrophage colony stimulating factor stimulate human macrophages to restrict growth of virulent Mycobacterium avium and to kill M. avium: killing effect mechanism depends on the generation of reactive nitrogen intermediates. J. Leukoc. Biol., 49, 380–387.PubMedGoogle Scholar
  40. Doherty T. M. and Sher A. (1997): Defects in cell-mediated immunity after chronic, but not innate, resistance of mice to Mycobacterium avium infection. J. Immunol., 158, 4822–4831.PubMedGoogle Scholar
  41. Dorman S. E. and Holland S. M. (1998): Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. J. Clin. Invest., 101, 2364–2369.PubMedCrossRefGoogle Scholar
  42. Escuyer V., Haddad N., Frehel C. and Berche P. (1996): Molecular characterization of a surface-exposed superoxide dismutase of Mycobacterium avium. Microb. Pathog., 20, 41–55.PubMedCrossRefGoogle Scholar
  43. Falkinham J. O. 3rd. (1996): Epidemiology of infection by nontuberculous mycobacteria. Clin. Microbiol. Rev., 9, 177–215.PubMedGoogle Scholar
  44. Frehel C., de Chastellier C., Lang T. and Rastogi N. (1986): Evidence for inhibition of fusion of lysosomal and prelysosomal compartments with phagosomes in macrophages infected with pathogenic Mycobacterium avium. Infect. Immun., 52, 252–262.PubMedGoogle Scholar
  45. Fujimura Y. (1986): Functional morphology of microfold cells (M cells) in Peyer’s patches-phagocytosis and transport of BCG by M cells into rabbit Peyer’s patches. Gastroenterol. Jpn., 21, 325–335.PubMedGoogle Scholar
  46. Glover N., Holzman A., Aronson T., Proman B., Berlin G. W., Dominguez P., Konzel K. A., Overturf G., Stelma G., Smith C. and Yaknes M. (1994): The isolation and identification of Mycobacterium avium complex recovered from Los Angeles potable water, a possible source of infection in AIDS patients. Int. J. Environ. Health Res., 4, 63–72.CrossRefGoogle Scholar
  47. Gomes M. S., Florido M., Pais T. F. and Appelberg R. (1999a): Improved clearance of Mycobacterium avium upon disruption of the inducible nitric oxide synthase gene. J. Immunol., 162, 6734–6739.PubMedGoogle Scholar
  48. Gomes M. S., Paul S., Moreira A. L., Appelberg R., Rabinovitch M. and Kaplan G. (1999b): Survival of Mycobacterium avium and Mycobacterium tuberculosis in acidified vacuoles of murine macrophages. Infect. Immun., 67, 3199–3206.PubMedGoogle Scholar
  49. Gruenheid S., Canonne-Hergaux F., Gauthier S., Hackam D. J., Grinstein S. and Gros P. (1999): The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J. Exp. Med., 189, 831–841.PubMedCrossRefGoogle Scholar
  50. Hackam D. J., Rotstein O. D., Zhang W., Gruenheid S., Gros R. and Grinstein S. (1998): Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nrampl) impairs phagosomal acidification. J. Exp. Med., 188, 351–364.PubMedCrossRefGoogle Scholar
  51. Hubbard R. D., Flory C. M. and Collins E. M. (1992): T-cell immune responses in Mycobacterium avium-infected mice. Infect. Immun., 60, 150–153.PubMedGoogle Scholar
  52. Inderlied C. B., Kemper C. A. and Bermudez L. E. (1993): The Mycobacterium avium complex. Clin. Microbiol. Rev., 6, 266–310.PubMedGoogle Scholar
  53. Iseman M. D. (1989): Mycobacterium avium complex and the normal host: the other side of the coin. N. Engl. J. Med., 321, 896–898.Google Scholar
  54. Jacobson M. A., Hopewell R. C., Yajko D. M., Hadley W. K., Lazarus E., Mohanty R. K., Modin G. W., Feigal D. W., Cusick R. S. and Sande M. A. (1991): Natural history of disseminated Mycobacterium avium complex infection in AIDS. J. Infect. Dis., 164, 994–998.PubMedCrossRefGoogle Scholar
  55. Jepson M. A. and Clark M. A. (1998): Studying M cells and their role in infection. Trends Microbiol., 6, 359–365.PubMedCrossRefGoogle Scholar
  56. Jung H. C., Eckmann L., Yang S. K., Panja A., Fierer J., Morzycka-Wroblewska E. and Kagnoff M. R (1995): A distinct array of pro-inflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J. Clin. Invest., 95, 55–65.PubMedCrossRefGoogle Scholar
  57. Kemper C. A., Bermudez L. E. and Deresinski S. C. (1998): Immunomodulatory treatment of Mycobacterium avium complex bacteremia in patients with AIDS by use of recombinant granulocyte-macrophage colony-stimulating factor. J. Infect. Dis., 177, 914–920.PubMedCrossRefGoogle Scholar
  58. Kim S. Y., Goodman J. R., Petrofsky M. and Bermudez L. E. (1998): Mycobacterium avium infection of gut mucosa in mice associated with late inflammatory response and intestinal cell necrosis. J. Med. Microbiol., 47, 725–731.Google Scholar
  59. Kobayashi K., Kasama T., Yamazaki J., Hosaka M., Katsura T., Mochizuki T., Soejima K. and Nakamura R. M. (1995): Protection of mice from Mycobacterium avium infection by recombinant interleukin 12. Antimicrob. Agents Chemother., 39, 1369–1371.PubMedCrossRefGoogle Scholar
  60. Manpother M. E. and Sanger J. G. (1984): In vitro interaction of Mycobacterium avium with intestinal epithelial cells. Infect. Immun., 45, 67–73.Google Scholar
  61. Momotani E., Whipple D. L., Thiermann A. B. and Cheville N. E. (1988): The role of M cells and macrophages in the entrance of Mycobacterium paratuberculosis into domes of ileal Peyer’s patches in calves. Vet. Pathol., 25, 131–137.PubMedCrossRefGoogle Scholar
  62. Newman G. W., Kelley T. G., Gan H. and Remold H. (1993): Concurrent infection of human macrophages with HIV-1 and Mycobacterium avium results in decreased cell viability, increase M. avium multiplication and altered cytokine production. J. Immunol., 151, 2261–2272.PubMedGoogle Scholar
  63. Ogata K., Linzer B. A., Zuberia R. I., Ganz T., Weber R. and Catanzaro A. (1992): Activity of defensins from human neutrophilic granulocytes against M. avium-M. intracellulare. Infect. Immun., 60, 4720–4725.PubMedGoogle Scholar
  64. Sangari F. and Bermudez L. E. (1999): Cloning of the kdp transport system of Mycobacterim avium. ASM General Meeting.Google Scholar
  65. Sangari F., Goodman J. R. and Bermudez L. E. (2000): Ultrastructural study of Mycobacterium avium infection of HT-29 human intestinal epithelial cells. J. Med. Microbiol., 49, 139–147.PubMedGoogle Scholar
  66. Sangari F. J., Petrofsky M. and Bermudez L. E. (1999): Mycobacterium avium infection of epithelial cells results in inhibition or delay in the release of interleukin-8 and RANTES. Infect. Immun., 67, 5069–5075.Google Scholar
  67. Sarmento A. and Appelberg R. (1996): Involvement of reactive oxygen intermediates in tumor necrosis factor alpha-dependent bacteriostasis of Mycobacterium avium. Infect. Immun., 64, 3224–3230.PubMedGoogle Scholar
  68. Saunders B. M. and Cheers C. (1995): Inflammatory response following intranasal infection with Mycobacterium avium complex: role of T-cell subsets and gamma interferon. Infect. Immun., 63, 2282–2287.PubMedGoogle Scholar
  69. Saunders B. M., Zhan Y. and Cheers C. (1995): Endogenous interleukin-12 is involved in resistance of mice to Mycobacterium avium complex infection. Infect. Immun., 63, 4011–4015.PubMedGoogle Scholar
  70. Schlesinger L. S. (1993): Macrophage phagocytosis of virulent but not attenuated strains of Mycobacterium tuberculosis is mediated by mannose receptors in addition to complement receptors. J. Immunol., 150, 2920–2930.PubMedGoogle Scholar
  71. Schlesinger L. S., Bellinger-Kawahara C. G., Payne N. R. and Horwitz M. A. (1990): Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3. J. Immunol., 144, 2771–2780.PubMedGoogle Scholar
  72. Schorey J. S., Carroll M. C. and Brown E. J. (1997): A macrophage invasion mechanism of pathogenic mycobacteria. Science, 277, 1091–1093.PubMedCrossRefGoogle Scholar
  73. Schorey J. S., Holsti M. A., Ratliff T. L., Allen P. M. and Brown E. J. (1996): Characterization of the fibronectin-attachment protein of Mycobacterium avium reveals a fibronectin-binding motif conserved among mycobacteria. Mol. Microbiol., 21, 321–329.PubMedCrossRefGoogle Scholar
  74. Shiratsuchi H., Johnson J. L., Toossi Z. and Ellner J. J. (1994): Modulation of the effector function of human monocytes for Mycobacterium avium by HIV-1 envelope glycoprotein 120. J. Clin. Invest., 93, 885–891.PubMedCrossRefGoogle Scholar
  75. Sturgill-Koszycki S., Schlesinger P. H., Chakraborty P., Haddix P. L., Collins H. L., Fok A. K., Allen R. D., Gluck S. L., Heuser J. and Russell D. G. (1994): Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase. Science, 263, 678–681.PubMedCrossRefGoogle Scholar
  76. Tokuraku K., Nakagawa H., Kishi E. and Kotani S. (1998): Human natural resistance-associated macrophage protein is a new type of microtubule-associated protein. FEBS Lett., 428, 63–67.PubMedCrossRefGoogle Scholar
  77. Wagner D., Parker A., Wu M. and Bermudez L. E. (1999): Cloning a putative iron transport gene in Mycobacterium avium. ASM General Meeting.Google Scholar
  78. Weinstein D. L., O’Neill B. L. and Metcalf E. S. (1997): Salmonella typhi stimulation of human intestinal epithelial cells induces secretion of epithelial cell-derived interleukin-6. Infect. Immun., 65, 395–404.Google Scholar
  79. Wolinsky E. (1979): Nontuberculous mycobacteria and associated diseases. Am. Rev. Respir. Dis., 119, 107–159.PubMedGoogle Scholar
  80. Wright S. D. and Silverstein S. (1983): Receptors for C3b and C3bi promote phagocytosis but not the release of toxic oxygen from human phagocytes. J. Exp. Med., 158, 2016–2026.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2001

Authors and Affiliations

  • Luiz E. Bermudez
    • 1
  • Dirk Wagner
    • 1
  • Danuta Sosnowska
    • 1
  1. 1.Kuzell Institute for Arthritis and Infectious DiseasesCalifornia Pacific Medical Center Research InstituteSan FranciscoUSA

Personalised recommendations