Department Head
Professor
College of Veterinary Medicine
College of Science: Department of Microbiology
105 Magruder Hall
College of Veterinary Medicine
Oregon State University
Corvallis, Oregon 97331-4801
541-737-6532 (reception)
541-737-2730 (fax)
cvm.biomed@oregonstate.edu
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.
Harriff MJ, Danelishvili L, Wu M, Wilder C, McNamara M, Kent ML, Bermudez LE. 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. 2009;191(4):1132-42.
Alonso-Hearn M, Patel D, Danelishvili L, Meunier-Goddik L, Bermudez LE. The Mycobacterium avium subsp. paratuberculosis MAP3464 gene encodes an oxidoreductase involved in invasion of bovine epithelial cells through the activation of host cell Cdc42. Infect Immun. 2008;76(1):170-8.
Danelishvili L, Wu M, Stang B, Harriff M, Cirillo SL, Cirillo JD, Bildfell R, Arbogast B, Bermudez LE. Identification of Mycobacterium avium pathogenicity island important for macrophage and amoeba infection. Proc Natl Acad Sci U S A. 2007;104(26):11038-43.
Harriff MJ, Bermudez LE, Kent ML. Experimental exposure of zebrafish, Danio rerio (Hamilton), 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. 2007;30(10):587-600.
Patel D, Danelishvili L, Yamazaki Y, Alonso M, Paustian ML, Bannantine JP, Meunier-Goddik L, Bermudez LE. 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. 2006;74(5):2849-55.
Tenant R, Bermudez LE. Mycobacterium avium genes upregulated upon infection of Acanthamoeba castellanii demonstrate a common response to the intracellular environment. Curr Microbiol. 2006;52(2):128-33.
Yamazaki Y, Danelishvili L, Wu M, Hidaka E, Katsuyama T, Stang B, Petrofsky M, Bildfell R, Bermudez LE. The ability to form biofilm influences Mycobacterium avium invasion and translocation of bronchial epithelial cells. Cell Microbiol. 2006;8(5):806-14.
Yamazaki Y, Danelishvili L, Wu M, Macnab M, Bermudez LE. Mycobacterium avium genes associated with the ability to form a biofilm. Appl Environ Microbiol. 2006;72(1):819-25.
Wagner D, Maser J, Lai B, Cai Z, Barry CE 3rd, Höner Zu Bentrup K, Russell DG, Bermudez LE. Elemental analysis of Mycobacterium avium-, Mycobacterium tuberculosis-, and Mycobacterium smegmatis-containing phagosomes indicates pathogen-induced microenvironments within the host cell's endosomal system. J Immunol. 2005;174(3):1491-500.
Dam T, Danelishvili L, Wu M, Bermudez LE. The fadD2 gene is required for efficient Mycobacterium avium invasion of mucosal epithelial cells. J Infect Dis. 2006;193(8):1135-42.
Li Y, Miltner E, Wu M, Petrofsky M, Bermudez LE. A Mycobacterium avium PPE gene is associated with the ability of the bacterium to grow in macrophages and virulence in mice. Cell Microbiol. 2005;7(4):539-48.
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. 2005;73(5):2621-7.
Miltner E, Daroogheh K, Mehta PK, Cirillo SL, Cirillo JD, Bermudez LE. Identification of Mycobacterium avium genes that affect invasion of the intestinal epithelium. Infect Immun. 2005;73(7):4214-21.
McGarvey JA, Wagner D, Bermudez LE. Differential gene expression in mononuclear phagocytes infected with pathogenic and non-pathogenic mycobacteria. Clin Exp Immunol. 2004;136(3):490-500.
Carter G, Wu M, Drummond DC, Bermudez LE. Characterization of biofilm formation by clinical isolates of Mycobacterium avium. J Med Microbiol. 2003;52(Pt 9):747-52.
Danelishvili L, McGarvey J, Li YJ, Bermudez LE. Mycobacterium tuberculosis infection causes different levels of apoptosis and necrosis in human macrophages and alveolar epithelial cells. Cell Microbiol. 2003;5(9):649-60.
Bannantine JP, Huntley JF, Miltner E, Stabel JR, Bermudez LE. The Mycobacterium avium subsp. paratuberculosis 35 kDa protein plays a role in invasion of bovine epithelial cells. Microbiology. 2003;149(Pt 8):2061-9.
Wagner D, Sangari FJ, Kim S, Petrofsky M, Bermudez LE. Mycobacterium avium infection of macrophages results in progressive suppression of interleukin-12 production in vitro and in vivo. J Leukoc Biol. 2002;71(1):80-8.
Bermudez LE, Sangari FJ, Kolonoski P, Petrofsky M, Goodman J. The efficiency of the translocation of Mycobacterium tuberculosis across a bilayer of epithelial and endothelial cells as a model of the alveolar wall is a consequence of transport within mononuclear phagocytes and invasion of alveolar epithelial cells. Infect Immun. 2002;70(1):140-6.
Li YJ, Petrofsky M, Bermudez LE. Mycobacterium tuberculosis uptake by recipient host macrophages is influenced by environmental conditions in the granuloma of the infectious individual and is associated with impaired production of interleukin-12 and tumor necrosis factor alpha. Infect Immun. 2002;70(11):6223-30.
Broxmeyer L, Sosnowska D, Miltner E, Chacón O, Wagner D, McGarvey J, Barletta RG, Bermudez LE. Killing of Mycobacterium avium and Mycobacterium tuberculosis by a mycobacteriophage delivered by a nonvirulent mycobacterium: a model for phage therapy of intracellular bacterial pathogens. J Infect Dis. 2002;186(8):1155-60.
Bermudez LE, Sangari FJ. Cellular and molecular mechanisms of internalization of mycobacteria by host cells. Microbes Infect. 2001;3(1):37-42.
Sangari FJ, Goodman J, Petrofsky M, Kolonoski P, Bermudez LE. Mycobacterium avium invades the intestinal mucosa primarily by interacting with enterocytes. Infect Immun. 2001;69(3):1515-20.
Roger PM, Bermudez LE. Infection of mice with Mycobacterium avium primes CD8+ lymphocytes for apoptosis upon exposure to macrophages. Clin Immunol. 2001;99(3):378-86.
McGarvey JA, Bermudez LE. Phenotypic and genomic analyses of the Mycobacterium avium complex reveal differences in gastrointestinal invasion and genomic composition. Infect Immun. 2001;69(12):7242-9.
Parker AE, Bermudez LE. Sequence and characterization of the glyceraldehyde-3-phosphate dehydrogenase of Mycobacterium avium: correlation with an epidermal growth factor binding protein. Microb Pathog. 2000;28(3):135-44.
Wu HS, Kolonoski P, Chang YY, Bermudez LE. Invasion of the brain and chronic central nervous system infection after systemic Mycobacterium avium complex infection in mice. Infect Immun. 2000;68(5):2979-84.
Miltner EC, Bermudez LE. Mycobacterium avium grown in Acanthamoeba castellanii is protected from the effects of antimicrobials. Antimicrob Agents Chemother. 2000;44(7):1990-4.
Mohagheghpour N, van Vollenhoven A, Goodman J, Bermudez LE. Interaction of Mycobacterium avium with human monocyte-derived dendritic cells. Infect Immun. 2000;68(10):5824-9.
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, expresses an invasive phenotype. Cell Microbiol. 2000;2(6):561-8.
Petrofsky M, Bermudez LE. Neutrophils from Mycobacterium avium-infected mice produce TNF-alpha, IL-12, and IL-1 beta and have a putative role in early host response. Clin Immunol. 1999;91(3):354-8.
Bermudez LE, Goodman J, Petrofsky M. Role of complement receptors in uptake of Mycobacterium avium by macrophages in vivo: evidence from studies using CD18-deficient mice. Infect Immun. 1999;67(9):4912-6.
Sangari FJ, Petrofsky M, Bermudez LE. Mycobacterium avium infection of epithelial cells results in inhibition or delay in the release of interleukin-8 and RANTES. Infect Immun. 1999;67(10):5069-75.
Bermudez LE, Parker A, Goodman JR. Growth within macrophages increases the efficiency of Mycobacterium avium in invading other macrophages by a complement receptor-independent pathway. Infect Immun. 1997;65(5):1916-25.
Bermudez LE, Petrofsky M, Goodman J. Exposure to low oxygen tension and increased osmolarity enhance the ability of Mycobacterium avium to enter intestinal epithelial (HT-29) cells. Infect Immun. 1997;65(9):3768-73.
Cirillo JD, Falkow S, Tompkins LS, Bermudez LE. Interaction of Mycobacterium avium with environmental amoebae enhances virulence. Infect Immun. 1997;65(9):3759-67.
Bermudez LE, Goodman J. Mycobacterium tuberculosis invades and replicates within type II alveolar cells. Infect Immun. 1996;64(4):1400-6.
Bermudez LE, Young LS. Factors affecting invasion of HT-29 and HEp-2 epithelial cells by organisms of the Mycobacterium avium complex. Infect Immun. 1994;62(5):2021-6.
Bermudez LE. Production of transforming growth factor-beta by Mycobacterium avium-infected human macrophages is associated with unresponsiveness to IFN-gamma. J Immunol. 1993;150(5):1838-45.
Bermudez LE, Petrofsky M, Kolonoski P, Young LS. An animal model of Mycobacterium avium complex disseminated infection after colonization of the intestinal tract. J Infect Dis 1992;165(1):75-9.
Bermudez LE, Young LS, Enkel H. Interaction of Mycobacterium avium complex with human macrophages: roles of membrane receptors and serum proteins. Infect Immun. 1991;59(5):1697-702.
