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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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
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
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
Early, Julie; Bermudez, Luiz E (2011) Mimicry of the pathogenic mycobacterium vacuole in vitro elicits the bacterial intracellular phenotype, including early-onset macrophage death. Infect Immun 79:2412-22
McNabe, M; Tennant, R; Danelishvili, L et al. (2011) Mycobacterium avium ssp. hominissuis biofilm is composed of distinct phenotypes and influenced by the presence of antimicrobials. Clin Microbiol Infect 17:697-703
Early, Julie; Fischer, Kay; Bermudez, Luiz E (2011) Mycobacterium avium uses apoptotic macrophages as tools for spreading. Microb Pathog 50:132-9
Li, Yong-jun; Danelishvili, Lia; Wagner, Dirk et al. (2010) Identification of virulence determinants of Mycobacterium avium that impact on the ability to resist host killing mechanisms. J Med Microbiol 59:8-16
Jha, Samradhni S; Danelishvili, Lia; Wagner, Dirk et al. (2010) Virulence-related Mycobacterium avium subsp hominissuis MAV_2928 gene is associated with vacuole remodeling in macrophages. BMC Microbiol 10:100
Harriff, Melanie J; Danelishvili, Lia; Wu, Martin et al. (2009) Mycobacterium avium genes MAV_5138 and MAV_3679 are transcriptional regulators that play a role in invasion of epithelial cells, in part by their regulation of CipA, a putative surface protein interacting with host cell signaling pathways. J Bacteriol 191:1132-42
Harriff, Melanie J; Wu, Martin; Kent, Michael L et al. (2008) Species of environmental mycobacteria differ in their abilities to grow in human, mouse, and carp macrophages and with regard to the presence of mycobacterial virulence genes, as observed by DNA microarray hybridization. Appl Environ Microbiol 74:275-85

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