Tom G. Obrig
Microbiology and Immunology
1962: B.S., West Virginia University
1969: Ph.D., University of Illinois at Urbana
1963-1964: Staff Scientist, Solvay Chemical Co., Syracuse, N.Y.
1964-1969: Graduate Student, U. of Illinois, with David Gottlieb,
1970-1972: NIH Postdoctorate, Dept. of Chem., U. of Texas, Austin, with Boyd Hardesty.
1973-1976: Penn Plan Fellow, Dept. of Biochem. and Biophys., Univ. of Penn, Phila., with James Ferguson.
1977-1980: Asst. Professor., Department of Pharmacology and Exptl. Therapeutics, Albany Medical College, Albany, New York.
1980-1983: Asst. Professor, Department of Biochemistry, Albany Medical College, Albany, NY.
1983-1988: Assoc. Professor, Dept. Microbiol. & Immunol., Albany Med Coll., Albany, NY.
1987-1990: Adjunct Associate Professor, Dept. of Biol. Sci., NYS Sch. Public Hlth., Albany. NY.
1988-1990: Professor, Dept. of Microbiol. & Immunol., Albany Med. Coll., Albany, NY.
1990-1998: Sr. Scientist, Dept. Microbiol. & Immunol., Univ. of Rochester Sch. Med, Rochester,NY.
1998-2008: Professor of Research, Dept. of Medicine/ Nephrology, Univ. of Virginia, Charlottesville.
2008-Present: Professor, Dept. Microbiology & Immunology, Univ. of Maryland School of Medicine.
The focus of my laboratory is the mode of action of Shiga toxins (Stx1, Stx2) from enterohemorrhagic E. coli O157:H7 (EHEC) and development of new mechansism-based therapeutics to minimize the dangerous and life-threatening host responses to this pathogen. EHEC is a food-borne pathogen that leads to kidney failure and central nervous system disorders in humans widely known as the hemolytic uremic syndrome, HUS. We have developed a Stx2-dependent murine model of HUS that displays most of the features of HUS in humans. Through the combined use of gene microarrays, protein analysis, immunohistochemistry, confocal microscopy, and kidney function tests, we have identified several new therapeutic targets in the murine model of HUS. No therapeutics are presently available for treatment of this HUS in humans. Thus, we are currently testing six or more different theraputic agents, each with defined modes of action to counteract the microvascular coagulation, thrombosis and renal failure of HUS. Each of these agents have shown promising activity in curtailing different phases of the disease process. For example, we have now reported that Stx2 targets specific tubule cells in the kidneys, resulting in apoptosis of this cell type and contributing to renal failure. An inhibitor of apoptosis presented systemically post-Stx2 exposure appears to prevent the death of these cells and facilitates the rescue of these animals from overt renal failure. A goal of future studies is the testing of therapeutic combinations to prevent both the Stx2-induced vascular changes as well as the direct damage to renal tubule cells. It should be noted that these studies have been carried out by a number of very talented graudate students, postdoctorates and technicians in the laboratory.
Selected Peer-Reviewed Publications (of 59)
Brown, J.E., Obrig, T.G., Ussery, M.A., and Moran, T.P. (1986). Shiga toxin from S. dysenteriae 1 inhibits protein synthesis in reticulocyte lysates by inactivation of aa-tRNA binding. Microb. Pathog 1:325-334.
Obrig, T.G., Del Vecchio, P.J., Karmali, M.A., Petric, M., Moran, T.P. and Judge, T.K. (1987). Pathogenesis of haemolytic uraemic syndrome. Lancet ii:687.
Obrig, T.G., Moran, T.P. and Brown, J.E. (1987). The mode of action of Shiga toxin on peptide elongation of eukaryotic protein synthesis. Biochem. J. 244:287-294.
Obrig, T.G., Del Vecchio, P.J., Brown, J.E., Moran, T.P., Rowland, B.M., Judge, T.K. and Rothman, S.W.(1988). Direct cytotoxic action of Shiga toxin on human vascular endothelial cells. Infect. Immun. 56:2373-2378.
Louise, C.B. and Obrig, T.G. (1991). Shiga toxin-associated hemolytic uremic syndrome: combined cytotoxic effects of Shiga toxin, interleukin-1 beta, and tumor necrosis factor-alpha on human vascular endothelial cells in vitro. Infect. and Immun. 59:4173-4179.
Louise, C.B. and Obrig, T.G. (1992). Shiga toxin-associated hemolytic uremic syndrome: combined cytotoxic effects of Shiga toxin and lipopolysacharide (endotoxin) on human vascular endothelial cells in vitro. Infect. and Immun. 60:1536-1543.
Obrig, T.G., Louise, C.B., Lingwood, C.A., Boyd, B., Barley-Maloney, L., and Daniel, T.O. (1993). Endothelial heterogeneity in Shiga toxin receptors and responses. J. Biol. Chem. 268:15484-88.
Kaye, S.A., Louise, C.B., Boyd, B., Lingwood, C.A., and Obrig, T.G. (1993). Shiga toxin-associated hemolytic uremic syndrome: Interleukin-1 beta enhancement of Shiga toxin cytotoxicity toward human vascular endothelial cells, in vitro. Infect. and Immun. 61:3886-3891.
Louise, C.B., and Obrig, T.G. (1994). Human renal microvascular endothelial cells as a potential target in the development of hemolytic uremic syndrome as related to fibrinolysis factor expression, in vitro. Microvascular Res. 47:377-387.
Louise, C.B., Moran, T.P., Lingwood, C.A., Del Vecchio, P.J., Culp, D. J., and Obrig, T.G. (1995) Binding of [125I]Shiga-like toxin-1 to human endothelial cells: implications for the pathogenesis of Shiga toxin-associated hemolytic uremic syndrome. Endothelium 3:159-170.
Kaye, S.A. and Obrig, T.G. (1995) Effect of TNF-alpha, Shiga toxin and calcium ionophore on Weibel-Palade body content of endothelial cells: possible implications for the hemolytic uremic syndrome. Thrombosis Res. 79:415-421.
Louise, C.B. and Obrig, T.G. (1995). Specific interaction of E. coli O157:H7-derived Shiga-like toxin-2 with human renal endothelial cells. J. Infect. Dis. 172:1397-1401.
Obrig, T.G. (1997) Shiga toxin mode of action in E. coli O157:H7 disease. Frontiers Biosci. 2:d635-642.
Louise, C.B., Tran, M.C., and Obrig, T.G. (1997). Sensitization of human umbilical vein endothelial cells to Shiga toxin: Involvement of protein kinase C and NF-kappa B. Infect. Immun. 65:3337-3344.
Viisorenanu, V., Polanowska-Grabowska, R., Suittitanamongkol, S., Obrig, T.G. and Gear. A.R.L.. (2000) Human platelet aggregation is not altered by Shiga toxin1 and 2. Thrombosis . Haemost. 98:403-410.
Fujii, J., Kinoshita, Y., Yutsudo, T., Taniguchi, H., Obrig, T., and Yoshida, S. (2001) Toxicity of Shiga toxin 1 in the central nervous system of rabbits. Infect. Immun. 69:6545-6548.
Andreoli SP, Trachtman H, Acheson DW, Siegler RL, Obrig TG. (2002) Hemolytic uremic syndrome: epidemiology, pathophysiology, and therapy. Pediatr Nephrol 17(4):293-8.
Fujii, J., Matsui, T., Heatherly, D.P., Schlegel, K.H., Lobo, P.I., Yutsudo, T. and Obrig, T. (2003) Rapid apoptosis induced by Shiga toxin 1 (Stx1) in HeLa cells. Infect. Immun. 71:2724-2735.
Guessous, F., Marcinkiewicz, M., Polanwska-Grabowska, R., Keepers, T.R., Obrig, T., and Gear, A.R.L. (2005) Shiga toxin 2 and LPS cause monocytic THP-1 cells to release factors which activate platelets. Thromb. Haemost. 94:1019-1027.
Guessous, F., Marcinkiewicz, M., Polanwska-Grabowska, R., Kongkhum, S., Heatherly, D., Obrig, T., and Gear, A.R.L. (2005) Shiga toxin 2 and LPS induce human microvascular endothelial cells to release chemokines and factors that stimulate platelet function. Infect. Immun. 73:8306-8316.
Roche, J.K., Gross, L.K., Keepers, T.R., Seaner, R.M., and Obrig, T.G. (2007) CXCL1/KC and CXCL2/MIP-2 are critical effectors and potential targets for therapy of E. coli 0157:H7-associated renal inflammation. Am. J. Pathol. 170: 526-537.
Keepers, T.R., Psotka, M.A., Gross, L.K., and Obrig, T.G. (2006) A Murine model of HUS: Shiga toxin with lipopolysaccharide mimics the renal damage and physiologic response of human disease. J. Am Soc. Nephrol. 17:3404-3414.
Keepers, T.R., Gross, L.K., and Obrig, T.G. (2007) MCP-1, MIP-1Î±, and RANTES recruit macrophages to the kidney in a mouse model of hemolytic uremic syndrome (HUS). Infect. Immun. 75:1229-1236.
Stone, M. K., Kolling, G.L., Lindner, M.H., and Obrig, T.G. (2008) p38 MAPK Mediates LPS & TNFÎ± induction of Stx2 sensitivity in HUVEC. Infect. Immun. 76: 1115-1121.
Obata, F., Tohyama, K., Bonev, A.D., Kolling, G., Keepers, T.R., Gross,L.K., Nelson, M.T., Sato, S. and Obrig, T.G.. (2008) Shiga toxin affects the central nervous system through receptor Gb3 localized to neurons. J. Infect. Dis. 198:1398-1406..
Jandhyala, D.M., Ahuwalia, A., Obrig, T., and Thorpe, CM. (2008) ZAK: A MAP3Kinase that transduces Shiga toxin and ricin induced proinflammatory cytokine expression. Cellular Microbiol. 10: 1468-1477.
Kolling, G.L., Obata, F., Gross, L.K., and Obrig, T.G. (2008) "Immunohistologic Techniques for Detecting the Glycolipid, Gb3, in the Mouse Kidney and Nervous Systems". Histochem. Cell Biol. 130: 157-164.
Moore, C.C., Martin, E.N., Lee, G.H., Obrig, T.G., Linden, J., Scheld, W.M. (2008) An A2a adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine septic shock models. BMC Infect. Dis. 8:141.
Fujii, J., Wood, K., Matsuda, F., Carneiro-Filho B.A., Schlegel, K.H., Yutsudo, T., Binnington-Boyd, B., Lingwood, C.A., Obata, F., Kim, K.S., Yoshida, S., Obrig, T. (2008) Shiga toxin 2 causes apoptosis in human brain microvascular endothelial cells via C/EBP homologous protein. Infect. Immun. 76: 3679-3689.
Psotka, M.A., Obata, F., Gross, L.K., and Obrig, T.G., (2009) Shiga Toxin 2 Targets the Murine Renal Collecting Duct Epithelium. Infect. Immun. (in press.).
Roche, J.K., Stone, M.K., Gross, L.K., Lindner, M., Seaner, R., Pincus, S.H., and Obrig, T.G. (2008) Post-exposure targeting of specific epitopes on ricin abrogates toxin-induced hypoglycemia, hepatic injury and lethality in a mouse model. Lab. Invest. 88:1178-1191.