Mycobacteria, Pathogenesis, Diseases, Intracellular Pathogens, Macrophage, Epithelial Mucosal Cells
VMB 630 Mechanisms of Disease; VMB 769 Animal Genomics; VMB 719 Physiology
The laboratory of Dr. Bermudez is interested in the mechanisms of the 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 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 experimental model systems.
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 mucosa, use signal transduction pathways to advantage, and surpass the host immune response.
Recently, we began 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. Interns in the laboratory are exposed to a number of techniques in cell and molecular biology, several models of bacterial infection and bioinformatics.
M.D., University of Rio de Janeiro, Brazil
- Curran, K., Leeper, H., O’Reilly, K., Jacob, J., and Bermudez, L.E. 2021. An analysis of the infections and determination of empiric antibiotic therapy in cats and dogs with cancer-associated infections. Antibiotics (Basel) micpaath.2021.104977.
- Keefe, B.F., Leestemaker-Palmer, A., and Bermudez, L.E. 2021. Mycobacterium avium subsp. hominissuis (MAH) microaggregate induction of host innate immunity is linked to biofilm formation. Microb. Pathogenesis; micpath.2021.104977.
- Phillips, I.L., Danelishvili, L., and Bermudez, L.E. 2021. Macrophage proteome analysis at different stages of Mycobacterium avium subsp. paratuberculosis infection reveals a mechanism of pathogen dissemination. Proteomes 9(2):20.
- Danelishvili, L., Armstrong, E., Miyasako, E., Jeffrey, B., and Bermudez, L.E. 2021. Exposure of Mycobacterium avium subsp. homonissuis to metal concentrations of the phagosome environment enhances the selection of persistent subpopulation to antibiotic treatment. Antibiotics (Basel). 9(12):927.
- Phillips, I.L., Everman, J.L., Bermudez, L.E., and Danelishvili, L. 2021. Acanthamoeba castellanii as a screening tool for Mycobacterium avium subsp. paratuberculosis virulence factors with relevance in macrophage infection. Microorganisms 8(10):1571.
- Silva, C., Rojony, R., Bermudez, L.E., Danelishvili, L. Short-chain fatty acids promote Mycobacterium avium subsp. hominissuis growth in nutrient-limited environments and influence susceptibility to antibiotics. Pathogens 9(9):700.
- Matos e Silva, C.A., Danelishvili, L., and Bermudez, L.E. 2020. Short-chain fatty acids promote Mycobacterium avium subsp. hominissuis growth in nutrient-limited environment and influence susceptibility to antibiotics. Pathogens 9:700.
- Palčeková, Z., Gilleron, M., Angala, S.K., Belardinelli, J.M., McNeil, M., Bermudez, L.E. and Jackson, M. 2020. Polysaccharide succinylation enhances the intracellular survival of Mycobacterium abscessus. ACS Infect. Dis. 6(8):2235-2248.
- Bechler, J. and Bermudez, L.E. 2020. Establishing the role of mucin as frontline defense of mucosal surfaces against Mycobacterium avium subsp. hominissuis. J. Pathogens 2020:1-7 ID 9451591.
- Rojony, R., Danelishvili, L., Campeau, A., Wozniak, J.M., Gonzalez, D.J., and Bermdez, L.E. 2020. Exposure of Mycobacterium abscessus supbsp abscessus to environmental stress and clinically used antibiotics reveals common proteome response among pathogenic mycobacteria. Microorganisms 8:698.
- Yingyu, C., Rose, S.J., Danelishvili, L., and Bermudez, L.E. 2019. Exposure to granuloma-like conditions leads to the expression of novel surface antigens on Mycobacterial bovis BCG and enhanced Specific Mucosal Immune Response; Internat. J. Microbiol. V 2019 ID916271.
- Rojony, R., Martin, M. Campeau, A., Wozniak, J.M., Gonzalez, D.J., Jaiswal, P., Danelishvili, L., and Bermudez, L.E. 2019. Exposure of Mycobacterium avium subsp hominssuis to environmental conditions mimicking the host and antibiotics result in specific protein expression. Clin. Proteomics 16:39.
- Rojony, R., Campeau, M., Wozniak, J.M., Gonzalez, D.J., Jaiswal, P., Danelishvili, L, and Bermudez, L.E. 2019. Quantitative analysis of Mycobacterium avium subsp. hominissuis proteome in response to antibiotics and during exposure to different environmental conditions. Clin. Proteomics. 16:39.
- Shoen, H.R.C., Rose, S.J., Ramsey, S.A., de Morais, H., and Bermudez, L.E. 2019. Analysis of staphylococcus infections in a veterinary teaching hospital from 2012 to 2015. Comp. Immunol. Microbiol. Infect. Dis. doi:10.1016/j.cimid.2019.101322.
- Chen, Y., Daneishvili, L., Rose, S.J., and Bermudez, L.E. 2019. Mycobacterium bovis BCG surface antigens expressed under the granuloma-like conditions as potential inducers of the protective immunity. Int. J. Microbiol. PMIC 31281365. doi 10.1155/2019/9167271.
- Lewis, M.S., Danelishvili, L., Rose, S.J., and Bermudez, L.E. 2019. MAV 4644 interaction with the host Cathepsin Z protects Mycobacterium avium subsp. hominissuis from rapid macrophage killing. Microorg. 7(5). PMID 31117286.
- Chiplunkar, S.S., Silva, C.A., Bermudez, L.E., and Danelishvili, L. 2019. Characterization of membrane vesicles released by Mycobacterium avium in response to environment mimicking the macrophage phagosome. Future Microbiol. PMID 30757918.
- Daniel-Wayman, S., Abate, G., Barber, D.L., Bermudez, L.E., Coler, R.N., Cynamon, M.H., Daley, C.L., Davidson, R.M., Dick, T., Floto, R.A., Henkle, E., Holland, S.M., Jackson, M., Lee, R.E., Nuermberger, E.L., Olivier, K.N., Ordway, D.J., Prevots, D.R.,. Sacchetini, J.C., Salfinger, M., Sassetti, C.M., Sizemore, C.F., Winthrop, K.L., and Zelazny, A.M. 2018. Advancing translational science for pulmonary NTM infections: A roadmap for research. Am. J. Respir. Crit. Care Med. doi:10.1164/rccm.201807-1273PP.
- Danelishvili, L, Rojony, R., Carson, K.L., Palmer, A.L., Rose, S.J., and Bermudez, L.E. 2018. Mycobacterium avium subsp. hominissuis effector MAVA5_06970 promotes rapid apoptosis in secondary-infected macrophages during cell-to-cell spread. Virulence 9(1):1287-1300.
- Blanchard, J.D., Elias, V., Cipolla, D., Gonda, I., and Bermudez, L.E. 2018. Effective treatment of the Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus sp. infections in macrophages, biofilm and in mice using Liposomal ciprofloxacin. Antimicrob. Agents Chemother. doi:10.1128/AAC.00440-18.
- Everman, J.L., Danelishvili, L., Flores, L.G., and Bermudez, L.E. 2018. MAP1203 Promotes Mycobacterium avium Subspecies paratuberculosis binding and invasion to bovine epithelial cells. Front Cell Infect. Microbiol. doi:10.3389/fcimb.2018.00217
- Bermudez, L.E., Rose, S.J., Everman, J.L., and Ziaie, N.R. 2018. Establishment of a host-to-host transmission model for Mycobacterium avium subsp. hominissuis using Caenorhabditis elegans and identification of colonization-associated genes. Front Cell Microbiol. doi:10.3389/fcimb.2018.00123.
- Babrak, L. and Bermudez, L.E. 2018. Response of the respiratory mucosal cells to Mycobacterium avium subsp. Hominissuis microaggregate. Arch. Microbiol. Jan. 30 PMID: 29383404.
- Danelishvili, L., Chinison, J.J., Pham, T., Gupta, R. and Bermudez, L.E. 2017. The voltage-dependent anion channels (VDAC) of mycobacterium avium hagosome are associated with bacterial survival and lipid export in macrophages. Sci. Rep. 7(1):7007.
- Jeffrey, B., Rose, S.J., Gilbert, K., Lewis, M., and Bermudez, L.E. 2017. Comparative analysis of the genomes of clinical isolates of Mycobacterium avium subsp. hominissuis regarding virulence-related genes. J. Med. Microbiol. doi:10.1099/jmm.0.000-507.
- Danelishvili, L., Shulzhenko, N., Chinison, J.J., Babrak, L., Hu, J., Morgun, A., Burrows, G., Bermudez, L.E. 2017. Mycobacterium tuberculosis proteome response to antituberculosis compounds reveals metabolic escape pathways that prolong bacterial survival. Antimicrob. Agents Chemother. doi:10.1128/AAC.00430-17.
- Zhao, M., Gilbert, K., Danelishvili, L., and Bermudez, L.E. 2016. Identification of prophages within the Mycobacterium avium 104 genome and the link of their function regarding to environment survival. Adv. in Microbiol. 6(13):927-941.
- Rose, S.J., and Bermudez, L.E. 2016. Identification of bicarbonate as a trigger involved with extracellular DNA export in mycobacterial biofilms. MBio. 7(6). pii:e01597-16. PMID: 27923918.
- Chinison, J.J., Danelishvili, L., Gupta, R., Rose, S.J., Babrak, L.M., and Bermudez, L.E. 2016. Identification of Mycobacterium avium subsp. hominissuis secreted proteins using an in vitro system mimicking the phagosomal environment. BMC Microbiol. 16(1):270.
- Danelishvili, L., Everman, J. and Bermudez, L.E. 2016. Mycobacterium tuberculosis PPE68 and Rv2626c genes contribute to the host cell necrosis and bacterial escape from macrophages. Virulence. 7(1):23-2.
- Everman, J.L., Ziaie, N.R., Bechler, J., and Bermudez, L.E. 2015. Establishing Caenorhabditis elegans as a model for Mycobacterium avium subspecies hominissuis infection and intestinal colonization. Biol. Open. 4(10):1330-5.
- Bermudez, L.E., Danelishvili, L., Babrack, L., and Pham, T. 2015. Evidence for genes associated with the ability of Mycrobacterium avium subsp. hominissuis to escape apoptotic macrophages. Front Cell Infect. Microbiol. 5:63. doi.10.3389/fcimb.2015.00063.
- Everman, J.L. and Bermudez, L.E. 2015. Antibodies against invasive phenotype-specific antigens increase Mycobacterium avium subspecies paratuberculosis translocation across a polarized epithelial cell model and enhance killing by bovine macrophages. Front Cell Infect. Microbiol. 5:58. doi.10.3389/fcimb.2015.00058.
- Babrak, L., Danelishvili, L., Rose, S.J., and Bermudez, L.E. 2015. Microaggregate-associated protein involved in invasion of epithelial cells by Mycobacterium avium subsp. hominissuis. Virulence. 6(7):694-703.
- Montezano, D., Meek, L., Gupta, R., Bermudez, L.E. and Bermudez, J.C. 2015. Flux balance analysis with objective function defined by proteomics data-metabolism of Mycobacterium tuberculosis exposed to mefloquine. PLoS One. 10(7):e0134014.
- Danelishvili, L. and Bermudez, L.E. 2015. Mycobacterium avium MAV 2941 mimics phosphoinositol-3-kinase to interfere with macrophage phagosome maturation. Microbes Infect. 17(9):628-37.
- Rose, S.J., Babrak, L.M. and Bermudez, L.E. 2015. Mycobacterium avium possesses extracellular DNA that contributes to biofilm formation, structural integrity, and tolerance to antibiotics. PLoS One. 10(5):e0128772.
- Magnusson, K.R., Hauck, L., Jeffrey, B.M., Elias, V., Humphrey, A., Nath, R., Perrone, A. and Bermudez, L.E. 2015. Relationships between diet-related changes in the gut microbiome and cognitive flexibility. Neuroscience. 300:128-40.
- Everman, J.L., Eckstein, T.M., Roussey, J., Coussens, P., Bannantine, J.P., and Bermudez, L.E. 2015. Characterization of the inflammatory phenotype of Mycobacterium avium subspecies paratuberculosis using a novel cell culture passage model. Microbiology 161(7):1420-34.
- Rose, S.J., Neville, M.E., Gupta, R., and Bermudez, L.E. 2014. Delivery of aerosolized liposomal amikacin as a novel approach for the treatment of nontuberculous mycobacteria in an experimental model of pulmonary infection. PLoS One 29:9(9); e108703.
- Babrak, L., Danelishvili, L., Rose, S.J., Kornberg, T. and Bermudez, L.E. 2014. The environment of Mycobacterium avium subsp. hominissuis Microaggregates induces the synthesis of small proteins associated with efficient infection of the respiratory epithelial cells. Infect. Immun. 83(2):625-36.
- Bannantine, J.P., Hines, M.E. 2nd, Bermudez, L.E., Talaat, A.M., Sreevatsan, S., Stabel, J.R., Chang, Y.F., Coussens, P.M., Barletta, R.G., Davis, W.C., Collins, D.M., Gröhn, Y.T., and Kapur, V. 2014. A rational framework for evaluating the next generation of vaccines against Mycobacterium avium subspecies paratuberculosis. Front Cell Infect. Microbiol. 4:126.
- Bermudez, L.E. and Meek, L. 2014. Mefloquine and its enantiomers are active against Mycrobacterium tuberculosis in vitro and in macrophages. Tuberc. Res. Treat. 530815, PMID: 25422262.
- Danelishvili, L. Stang, B., Bermudez, L.E. 2014. Identification of Mycrobacterium avium genes expressed during in vivo infection and the role of the oligopeptide transporter OppA in virulence. Microb. Pathog. Nov; 76:67-76.
- Danelishvili, L., Babrak, L., Rose, S.J., Everman, J. Bermudez, L.E. 2014. Mycrobacterium tuberculosis alters the metalloprotease activity of the COP9 signalosome. MBio. aug 19; 5(4). PMID 25139900.
- Bannantine, J.P., Everman, J.L., Rose, S.J., Babrak, L., Katani, R., Barletta, R.G., Talaat, A.M., Grohn, Y.T., Chang, Y.F., Kapur, V., Bermudez, L.E. 2014. Evaluation of eight liver attenuated vaccine candidates for protection against challenge with virulent Mycobacterium avium subspecies paratuberculosis in mice. Front Cell infect. Microbiol. 4:88.
- Motamedi, N., Danelishvili, L., Bermudez, L.E. 2014. Identification of Mycobacterium avium genes associated with resistance to host antimicrobial peptides. J. Med. Microbiol. 63(Pt 7):923-30.
- Sennoune, S.R., Bermudez, L.E., Lees, J.C. Hirsch, J., Filleur, S., Martinez-Zaguilan, R. 2014. Vacuolar H+-ATPase is down-regulated by the angiogenesis-inhibitory piement epithelium-derived factor in metastatic prostate cancer cells. Cell Mol. Biol. 60(1):45-52.
- Rose, S. and Bermudez, L.E. 2014. Mycobacterium avium biofilm attenuates human mononuclear phagocyte function by triggering hyper-stimulation and apoptosis during early infection. Infect. Immun. 82:405.
- McNamara, M.,Tzeng, S-C., Maier, C., Rose, S., Bermudez, L.E. 2013. Surface-exposed proteins of Mycobacteria and the role of Cu-Zn superoxide dismutase in macrophage and neutrophil survival. Proteome Sci. 11:45.
- Bannantine, J.P., Bermudez, L.E. 2013. No holes barred: Invasion of the intestingal mucosa by Mycobacterium avium subsp paratuberculosis. Infect. Immun. 81:2645.
- Danelishvili, L., McNamara, M., Tripathi, S., and Bermudez, L.E. 2013. (Submitted). Mycobacterium avium MAV_2941 interacts with the adaptor protein AP3B1 and competes for P13K altering phagosome maturation in macrophages.
- Danelishvili, L, Everman, J, McNamara, M, Bermudez, LE. 2012. Inhibition of plasma membrane-associated protease CatG by Mycobacterium tuberculosis Rv3364c suppresses caspase-1 and pyroptosis in macrophages. Frontiers Cell. and Infect. Microbiol. 2:1.
- Silva, C.A.M., Danelishvili, L., McNamara, M., Moreira, M., Bildfell, R., Almeida, T., Avellar, R., Oliveira, A., Bermudez, L.E., and Pessolani, M.C. 2013. (In Press). Mycobacterium leprae binds to and invades both nasal septum and alveolar epithelial cells using surface exposed proteins. Infect. Immun.
- Rose, S., Hill, R., Bermudez, L.E., and Miller-Morgan, T. 2013. Colonization of imported ornamental fish with potential fish and human bacterial pathogens, including antibiotic-resistant bacteria. J. Fish. Dis., Electronic publication.
- Wilberger, M.S., Anthony, K.E. Rose, S., McClain, M., and Bermudez, L.E. 2012. Beta-lactam antibiotic resistance among Enterobacter spp. isolated from infections in animals. Advances in Microbiology 2:129.
- Bermudez, L.E., Inderlied, C.B., Kolonoski, P., Chee, C.B., Aralar, P., Petrofsky, M., Parman, T., Green, C.E., Lewin, A.H., Ellis, W.Y., and Young, L.S. 2012. Identification of (+)-erythro-mefloquine as an active enantiomer with greater efficacy than mefloquine against Mycobacterium avium infection in mice. Antimicrob Agents Chemother. 56(8):4202-6.
- McNamara, M., Tzeng, S.C., Maier, C., Zhang, L., and Bermudez, L.E. 2012. Surface proteome of “Mycobacterium avium subsp. Hominissuis” during the early stages of macrophage infection. 2012. Infect. Immun. 80(5):1868-80.
- McNamara, M., Danelishvili, L. and Bermudez, L.E. 2012. The Mycobacterium avium PPE protein, MAV-2928, interacts with the ESAT-6 family protein MAV-2921 and localizes to the bacterial surface. Microbial Pathogenesis 52:227.
- Danelishvili, L., Everman, J., McNamara, M., and Bermudez, L.E. 2012. Inhibition of plasma-membrane-associated protease CatG by Mycobacterium tuberculosis Rv3364c suppresses caspase-1 and pyroptosis in macrophages. Frontiers Cellular and Infection Micro. 2:1.
- Danelishvili, L., Everman, J.L, McNamara, M.J., and Bermudez, L.E. 2011. Inhibition of the plasma-membrane-associated serine protease cathepsin G by Mycobacterium tuberculosis Rv3364c suppresses caspase-1 and pyroptosis in macrophages. Front Microbiol. 2:281.
- Bermudez, L.E. and Lizarraga, A.K. 2011. Operation smile: how to measure its success. Am. Plast. Surg. 67(3):205-8.
- Early, J. and Bermudez, L.L. 2011. Mimicry of the pathogenic mycobacterium vacuole in vitro elicits the bacterial intracellular phenotype, including early-onset macrophage death. Infect. Immun. 79(6):2412-22.
- Early, J., Fischer, K., and Bermudez, L.E. 2011. Mycobacterium avium uses apoptotic macrophages as tools for spreading. Microb. Pathog. 50 (2):132-9.
- McNabe, M., Tennant, R., Danelishvili, L., Young, L., and Bermudez, L.E. 2011. Mycobacterium avium ssp. Hominissuis biofilm is composed of distinct phenotypes and influenced by the presence of antimicrobials. Clin. Microbiol. Infect. 17(5):697-703.
- Bermudez, L.E., Petrofsky, M., Sommer, S., and Barletta, R.G. 2010. Peyer’s patch-deficient mice demonstrate that Mycobacterium avium subsp. Paratuberculosis translocates across the mucosal barrier via both M cells and enterocytes but has inefficient dissemination. Infect. Immun. 78(8):3570-7.
- Danelishvili, L., Yamazaki, Y., Selker, J., and Bermudez, L.L. 2012. Secreted Mycobacterium tuberculosis Rv3654c and Rv3655c proteins participate in the suppression of macrophage apoptosis. PLoS One 5(5):e10474.
- Jha, S.S, Danelshvili, L., Wagner, D., Maser, J., Li, Y.J., Moric, I., Vogt, S., Yamazaski, Y., Lai, B., and Bermudez, L.E. 2010. Virulence-related Mycobacterium avium subsp. Hominissuis MAV 2928 gene is associated with vacuole remodeling in macrophages. BMC Microbiol. 10:100.
- Whipps, C.M., Boorom, K., and Bermudez, L.E., Kent, M.L. 2010. Molecular characterization of Blastocystis species in Oregon identifies multiple subtypes. Parasitol. Res. 106(4):827-32.
- Li, Y.J., Danelishvili, L., Wagner, D. Petrofsky, M., and Bermudez, L.E. 2010. Identification of virulence determinants of Mycobacterium avium that impact on the ability to resist host killing mechanisms. J. Med. Microbiol. 59(Pt 1):8-16.
- Alonso-Hearn, M., Eckstein, T.J., Sommer, S., and Bermudez, L.E. 2010. A Mycobacterium avium subsp. Paratuberculosis LuxR regulates cell envelope and virulence. Innate Immun. 16(4):235-47.
- Chacon, O., Bermudez, L.E., Zinniel, D.K., Chahal, H.K., Fenton, R.J., Feng, Z., Hanford, K., Adams, L.G., and Barletta, R.G. 2009. Impairment of D-alanine biosynthesis in Mycobacterium smegmatis determines decreased intracellular survival in human macrophages. Microbiology 155(pt 5):1440-50.