Luiz Bermudez
Mycobacteria, Pathogenesis, Diseases, Intracellular Pathogen,
Macrophage, Epithelial Mucosal Cells
Luiz Bermudez, M.D.
College of Veterinary Medicine and
Department of Microbiology
M.D. 1978, University of Rio de Janerio, Brazil
Email: mailto:luiz.bermudez@oregonstate.edu
RESEARCH
The laboratory of Dr Bermudez is interested in the mechanisms of pathogenesis of intracellular bacteria, with focus on mycobacteria.
Mycobacteria are a common cause of infections in humans and animals. Mycobacterium tuberculosis infects a third of the world population and is responsible for 3 million deaths annually. Mycobacterium avium, an environmental bacterium, commonly causes disseminated disease in patients with Acquired Immunodeficiency Syndrome (AIDS), and pulmonary infection in patients with chronic lung disease, cystic fibrosis, and in elderly women. Mycobacterium avium subsp paratuberculosis is an important agriculture pathogen causing Johne’s disease, a wasting disease in cattle. Mycobacteria also infect fish, and a number of species have been isolated causing disease. The majority of the mycobacterial diseases have, as a hallmark, the formation of granulomas.
Mycobacteria are intracellular pathogens (with a few exceptions), which are able to replicate and survive within macrophages. They evolved pathogenic mechanisms that allow them to enter in macrophages (phagocytosis) by non-traditional pathways, inhibit acidification of the intracellular vacuole where they live, and prevent fusion of this vacuole with the bactericidal enzymes-loaded lysosomes. Our laboratory is interested in the mechanisms of uptake of mycobacteria by macrophages, both the first macrophage encountered by the bacterium, as well as the subsequent ones (as part of the dissemination process). We are also interested in mycobacterial genes required for the early events in the infection of macrophages, as well as in the spreading of the infection (dissemination) and an experimental model to study it.
The great majority of the pathogens need sophisticated means to cross the mucosal barrier before being able to cause infection. Mycobacteria are not an exception. M. tuberculosis crosses the respiratory mucosa; M. avium crosses both the respiratory and the intestinal mucosas, and M. paratuberculosis invades the intestinal mucosa in cattle. It is clear now that all these pathogens have evolved mechanisms to subvert the host pathways and are able to infect cells. Because mucosal epithelial cells are not phagocytic cells, the pathogen needs to manipulate the host cell (signal pathways and trafficking) to be able to enter and cross it. Our laboratory studies how the three mycobacteria cited above can cross the epithelial mucosa of the host. We use cell biology and molecular biology techniques for insights into how mycobacteria can invade the host mucosa, use signal transduction pathways to advantage, and surpass the host immune response.
Recently, we began to work on the mechanism of pathogenesis of two zoonoses, i.e., brucellosis and tularenia (Brucella abortus and Francisella tularensis). Our studies aim to identify how those pathogens interact with host innate immune response.
Trainees in the laboratory are exposed to a number of techniques in cell and molecular biology, several models of bacterial infection, and bioinformatics.
Selected Publications
Alonso-Hearn M, Patel D, Danelishvili L, Meunier-Goddik L, Bermudez LE. Mycobacterium avium subsp paratuberculosis 3464 gene encodes an oxireductase involved in invasion of bovine epithelial cell through the interaction with host cell Cdc42. Infect Immun 76: 170, 2008.
Harriff MJ, Wu M, Kent M, Bermudez LE. Species of environmental mycobacteria vary in their ability to grow in human, mouse and carp macrophages, and differ regarding the presence of virulence genes observed by DNA microarray hybridization. Appl Environmen Microbiol, 74: 275, 2008.
Danelishvili L, M Wu, B Stang, M Harriff, S Cirillo, J Cirillo, R Bildfell, B Arbogast, and LE Bermudez. Identification of Mycobacterium avium pathogenicity island important for macrophage and amoeba infection. Proceedings of the National Academy of Sciences of the United States of America 104:11038-11043, 2007.
Harriff M, L Bermudez, and ML Kent. Experimental exposure of zebrafish (Danio rerio) to Mycobacterium marinum and Mycobacterium peregrinum reveals the gastrointestinal tract as the primary route of infection: A potential model for environmental mycobacterial infection. J Fish Dis 29:1, 2007.
Patel D, L Danelishvili, Y Yamazaki, M Alonso, ML Paustian, J P Bannantine, L Meunier-Goddik, and LE Bermudez. The ability of Mycobacterium avium subsp. paratuberculosis to enter bovine epithelial cells is influenced by preexposure to a hyperosmolar environment and intracellular passage in bovine mammary epithelial cells. Infect Immun 74:2849-2855, 2006.
Tenant R, and LE Bermudez. Mycobacterium avium genes upregulated upon infection of Acanthamoeba castellanii demonstrate a common response to the intracellular environment. Current microbiology 52:128-133, 2006.
Yamazaki Y, L Danelishvili, M Wu, E Hidaka, T Katsuyama, B Stang, M Petrofsky, R Bildfell, and LE Bermudez. The ability to form biofilm influences Mycobacterium avium invasion and translocation of bronchial epithelial cells. Cell Microbiol 8:806-814, 2006.
Yamazaki Y, L Danelishvili, M Wu, M Macnab, and LE Bermudez. Mycobacterium avium genes associated with the ability to form a biofilm. Appl Environ Microbiol 72:819-825, 2006.
Wagner D, Maser J, Lai B, Cai Z, Barry III C, Bermudez LE. Measurements of the concentration of iron, calcium, nickel, potassium, copper, zinc, manganese, chlorine, phosphorus, and sulfur using X-ray microscopy in Mycobacterium avium, Mycobacterium tuberculosis and Mycobacterium smegmatis phagosomes reveals the presence of different environments. J Immunol 174:1491, 2005.
Dam T, Wu M, Bermudez LE. The fadD2 gene is required for efficient M. avium invasion of mucosal epithelial cells. J Infect Dis 193:1135, 2006.
Li Y, Miltner E, Wu M, Petrofsky M, Bermudez LE. Identification of a Mycobacterium avium PPE gene associated with the ability to inhibit phagolysosome fusion in vitro and virulence in vivo. Cell Microbiol 7:539, 2005.
Petrofsky M, Bermudez LE. CD4+ T cells but Not CD8+ or gammadelta+ lymphocytes are required for host protection against Mycobacterium avium infection and dissemination through the intestinal route. Infect Immun 73:2621, 2005.
Miltner E, Daroogheh K, Mehta PK, Cirillo SL, Cirillo JD, Bermudez LE. Identification of Mycobacterium avium genes associated with the invasion of mucosal epithelial cells. Infect Immun 73(7):4214, 2005.
McGarvey JA, Wagner D, Bermudez LE. Differential gene expression in mononuclear phagocytes infected with pathogenic and non-pathogenic mycobacteria. Infect Immun 136:490-500, 2004.
Carter G, Drummond D, Bermudez LE. Characterization of biofilm formation by Mycobacterium avium strains. J Med Microbiol 52:1-6, 2003.
Danelishvili L, McGarvey J, Li Y, Bermudez LE. Mycobacterium tuberculosis infection causes different levels of apoptosis and necrosis in human macrophages and alveolar epithelial cells. Cell Microbiol 5:649-60, 2003.
Bannantine JP, Huntley JF, Miltner E, Stabel J, Bermudez LE. The Mycobacterium avium subsp paratuberculosis 35kDa protein plays a role in invasion of bovine epithelial cells. Microbiology 149:2061, 2003.
Wagner D, Sangari FJ, Kim S, Petrofsky M, Bermudez LE. Mycobacterium avium infection of macrophages results in progressive suppression interleukin-12 production in vitro and in vivo. J Leukocyte Biol 71:80, 2002.
Bermudez LE, Kolonoski P, Goodman J, Petrofsky M. Translocation of Mycobacterium tuberculosis across a bi-layer model mimicking the alveolar wall is a consequence of transport within mononuclear phagocytes and invasion of alveolar epithelial cells. Infect Immun 70:140, 2002.
Li Y, Goodman J, Petrofsky M, Bermudez LE. Mycobacterium tuberculosis uptake by human macrophages is regulated by environmental conditions and results in impaired production of IL-12 and TNF-alpha. Infect Immun 70:6223-6230, 2002.
Broxmeyer LA, Sosnowska D, Miltner E, Chacon O, Wagner D, McGarvey J, Barletta R, Bermudez LE. Killing of Mycobacterium avium and Mycobacterium tuberculosis by mycobacteriophage delivered by a non-virulent mycobacterium: A model for phage therapy of Intracellular Bacterial Pathogens. J Infect Dis 186:1155, 2002.
Bermudez LE, Sangari FJ. Molecular mechanisms of mycobacterial invasion of mucosal epithelial cells. Microbes and Infection 3:37, 2001.
Sangari FJ, Goodman J, Petrofsky M, Bermudez LE. Mycobacterium avium invades the intestinal mucosa primarily by interacting with enterocytes. Infect Immun 69:1515, 2001.
Roger P-M, Bermudez LE. Infection of mice with Mycobacterium avium primes CD8+ lymphocyte for apoptosis upon exposure to macrophages. Clin Immunol 99:378, 2001.
McGarvey J, Bermudez LE. Identification of phenotypic and genomic difference involved in gastrointestinal invasion and dissemination among organisms of the Mycobacterium avium complex. Infect Immun 69:7242, 2001.
Parker A, Bermudez LE. Sequence and characterization of the glyceraldehyde-3-phosphate dehydrogenase of Mycobacterium avium: Correlation with an epidermal growth factor binding protein. Microbial Pathogenesis 28:135, 2000.
Wu H-S, Kolonoski P, Chang YY, Bermudez LE. Invasion of the Brain and chronic central nervous infection after systemic Mycobacterium avium complex infection in mice. Infect Immun 68:2979, 2000.
Miltner E, Bermudez LE. Mycobacterium avium growth in Acanthamoeba castellanii is protected from the effect of antimicrobials. Antimicrob Agents Chemother 44:1990, 2000.
Mohagheghpour N, Vollenholver A, Goodman J, Bermudez LE. Infection and Intracellular survival of Mycobacterium avium within human monocyte-derived dendritic cells. Infect Immun 68:5824, 2000.
Sangari FJ, Goodman J, Bermudez LE. Mycobacterium avium enters intestinal epithelial cells through the apical membrane but not by the basolateral surface, activates small GTPase Rho, and once within epithelial cells express an invasive phenotype. Cell Microbiol 2:561, 2000.
Petrofsky M, Bermudez LE. Neutrophils from Mycobacterium avium-infected mice produce TNF-a, IL-12 and IL-1ß and have a putative role in the early immune response. Clin Immunol 91:354, 1999.
Bermudez LE, Goodman J, Petrofsky M. Role of complement receptor in the uptake of Mycobacterium avium by macrophages in vivo: Evidence from studies using ß2 integrin knockout mice. Infect Immun 67:4912, 1999.
Sangari FJ, Petrofsky M, Bermudez LE. Mycobacterium avium infection of mucosal epithelial cells is associated with either suppression or delay of the release of IL-8 and RANTES. Infect Immun 67:5069, 1999.
Bermudez LE, Parker A, Goodman J. Growth within macrophage increases the efficiency of Mycobacterium avium to invade human macrophages by a complement receptor-independent pathway. Infect Immun 65:1916, 1997.
Bermudez LE, Petrofsky M, Goodman JR. Exposure to low concentrations of oxygen and increased osmolarity enhance the ability of Mycobacterium avium to enter intestinal epithelial (HT-29) cells. Infect Immun 65:3768, 1997.
Cirillo J, Falkow S, Tompkins L, Bermudez LE. Growth of Mycobacterium avium within environmental amoeba enhances virulence. Infect Immun 65:3759, 1997.
Bermudez LE, Goodman J. Mycobacterium tuberculosis invades and replicates within type II alveolar cells. Infect Immun 64:1400, 1996.
Bermudez LE, Young LS. Factors affecting invasion of HT-29 and HEp-2 epithelial cells by organisms of the Mycobacterium avium complex. Infect Immun 62:2021, 1994.
Bermudez LE. Production of transforming growth factor b1 by Mycobacterium avium infected macrophages is associated with unresponsiveness to interferon gamma. J Immunol 150:1838, 1993.
Bermudez LE, Petrofsky M, Kolonoski P, Young LS. An animal model of Mycobacterium avium complex disseminated infection following colonization of the intestinal tract. J Infect Dis 165:75, 1992.
Bermudez LE, Young LS, Enkel H. Interaction of Mycobacterium avium complex with macrophages: Roles of membrane receptors and serum proteins. Infect Immun 59:1697, 1991.