Mycobacterium avium causes infection in both immunocompromised patients and in healthy individuals. The chiefly encountered infections are in the respiratory tract, and disseminated. The ability of the bacterium to survive in different environments in the host requires tight gene regulation. During the past 4 years of this grant, we have unveiled a number of the complex aspects of M. avium interaction with the host, from the interaction between the bacterium and the host mucosa, to the ability to survive in macrophages and to disseminate. Several virulence genes were identified and their functions characterized. Many of the genes allow the bacterium to enter intestinal epithelial cells, and others are required for survival within macrophages. The long-term goal of this project is to understand the mechanisms of interaction between the pathogen and host cells. Our submission now contains proposed studies to explore the relationship between M. avium and macrophages. Our central hypothesis is that M. avium has specific strategies to subvert the host cells and that becoming aware of them will allow for improved means of prevention and treatment of M. avium-related diseases. We propose to continue this work during the next funding period by evaluating: 1. M. avium interference with macrophage killing mechanisms: (a) studying bacterial genes that participate in modifying/interfering with the mycobacterial vacuole formation upon uptake into macrophages;(b) studying the mechanisms of action of genes associated with bacterial resistance to macrophage killing mechanisms; 2. The mechanisms by which M. avium leaves apoptotic macrophages and spreads to surrounding macrophages.

Public Health Relevance

Mycobacterium avium is a significant pathogen in patients with AIDS and in individuals with chronic lung disease. M. avium forms biofilm and lives within macrophages. Only a few antimicrobials have activity against it. The knowledge about pathogenic mechanisms of infection is needed to improve effective therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Lambros, Chris
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Oregon State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Danelishvili, Lia; Chinison, Jessica J J; Pham, Tuan et al. (2017) The Voltage-Dependent Anion Channels (VDAC) of Mycobacterium avium phagosome are associated with bacterial survival and lipid export in macrophages. Sci Rep 7:7007
Winthrop, Kevin; Rivera, Andrea; Engelmann, Flora et al. (2016) A Rhesus Macaque Model of Pulmonary Nontuberculous Mycobacterial Disease. Am J Respir Cell Mol Biol 54:170-6
Babrak, Lmar; Danelishvili, Lia; Rose, Sasha J et al. (2015) The environment of ""Mycobacterium avium subsp. hominissuis"" microaggregates induces synthesis of small proteins associated with efficient infection of respiratory epithelial cells. Infect Immun 83:625-36
Babrak, Lmar; Danelishvili, Lia; Rose, Sasha J et al. (2015) Microaggregate-associated protein involved in invasion of epithelial cells by Mycobacterium avium subsp. hominissuis. Virulence 6:694-703
Bermudez, Luiz E; Danelishvili, Lia; Babrack, Lmar et al. (2015) Evidence for genes associated with the ability of Mycobacterium avium subsp. hominissuis to escape apoptotic macrophages. Front Cell Infect Microbiol 5:63
Danelishvili, Lia; Bermudez, Luiz E (2015) Mycobacterium avium MAV_2941 mimics phosphoinositol-3-kinase to interfere with macrophage phagosome maturation. Microbes Infect 17:628-37
Motamedi, Nima; Danelishvili, Lia; Bermudez, Luiz E (2014) Identification of Mycobacterium avium genes associated with resistance to host antimicrobial peptides. J Med Microbiol 63:923-30
Rose, Sasha J; Bermudez, Luiz E (2014) Mycobacterium avium biofilm attenuates mononuclear phagocyte function by triggering hyperstimulation and apoptosis during early infection. Infect Immun 82:405-12
Danelishvili, Lia; Stang, Bernadette; Bermudez, Luiz E (2014) Identification of Mycobacterium avium genes expressed during in vivo infection and the role of the oligopeptide transporter OppA in virulence. Microb Pathog 76:67-76
McNamara, Michael; Tzeng, Shin-Cheng; Maier, Claudia et al. (2012) Surface proteome of ""Mycobacterium avium subsp. hominissuis"" during the early stages of macrophage infection. Infect Immun 80:1868-80

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