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Mechanisms of Mycobacterium Avium Pathogenesis

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Inflammation

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Abstract

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.

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References

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Bermudez L. E. and Goodman J. (1996): Mycobacterium tuberculosis invades and replicates within type II alveolar cells. Infect. Immun., 64, 1400–1406.

    Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Bermudez L. E., Parker A. and Goodman J. R. (1997a): Growth within macrophages increas-

    Google Scholar 

  • es the efficiency of Mycobacterium avium in invading other macrophages by a complement receptor-independent pathway. Infect. Immun., 65, 1916–1925.

    Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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 

  • Bermudez L. E. and Young L. S. (1989): Oxidative and non-oxidative intracellular killing of Mycobacterium avium complex. Microb. Pathog., 7, 289–297.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Bermudez L. E. and Young L. S. (1991): Natural killer cell dependent mycobacteriostatic and mycobactericidal activity in human macrophages. J. Immunol., 146, 265–269.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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 

  • 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 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Falkinham J. O. 3rd. (1996): Epidemiology of infection by nontuberculous mycobacteria. Clin. Microbiol. Rev., 9, 177–215.

    PubMed  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Inderlied C. B., Kemper C. A. and Bermudez L. E. (1993): The Mycobacterium avium complex. Clin. Microbiol. Rev., 6, 266–310.

    PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Jepson M. A. and Clark M. A. (1998): Studying M cells and their role in infection. Trends Microbiol., 6, 359–365.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Sangari F. and Bermudez L. E. (1999): Cloning of the kdp transport system of Mycobacterim avium. ASM General Meeting.

    Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • Schorey J. S., Carroll M. C. and Brown E. J. (1997): A macrophage invasion mechanism of pathogenic mycobacteria. Science, 277, 1091–1093.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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 

  • Wolinsky E. (1979): Nontuberculous mycobacteria and associated diseases. Am. Rev. Respir. Dis., 119, 107–159.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

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  1. Kuzell Institute for Arthritis and Infectious Diseases, California Pacific Medical Center Research Institute, San Francisco, California, USA

    Luiz E. Bermudez, Dirk Wagner & Danuta Sosnowska

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  1. Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland

    Andrzej Górski , Hubert Krotkiewski  & Michał Zimecki ,  & 

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Bermudez, L.E., Wagner, D., Sosnowska, D. (2001). Mechanisms of Mycobacterium Avium Pathogenesis. In: Górski, A., Krotkiewski, H., Zimecki, M. (eds) Inflammation. Springer, Dordrecht. https://doi.org/10.1007/978-94-015-9702-9_12

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