Douglas Golenbock, M.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Infectious Diseases and Immunology
   Medicine
   Molecular Genetics and Microbiology

Other Affiliation(s):
   Center for AIDS Research
   Program in Immunology and Virology

Toll receptors, sepsis and malaria.

Dr Douglas Golenbock is a Professor of Medicine and Infectious Diseases and Chief of the Division of Infectious Diseases and Immunology at the University of Massachusetts Medical School.  The principal goal of Dr Golenbock´s laboratory is to characterize the receptors used by phagocytic leukocytes to respond to the presence of microbial products, thus resulting in acute and chronic inflammatory diseases. These include septic shock, pyogenic pneumonia, fatal viral infections and malaria.  A major focus of the laboratory is the effect of bacterial lipopolysaccharide (LPS) and the study of the family of its receptors, including the LPS binding proteins LBP and CD14, the Toll-like receptors (TLRs), and the TLR4 co receptor, MD-2.  Other microbial products of more recent interest to our group include bacterial and viral nucleic acid, malarial hemozoin and lipopeptides produced by Gram-positive bacteria.  The Golenbock laboratory uses a variety of approaches to study cellular activation by microbial products. Most of these involve modern molecular genetic techniques, and include the construction of heterologously expressing cell lines, both in established cell lines (e.g., CHO and HEK293) as well as immortalized macrophages.  Once these lines are constructed, we use them in biochemical, immunological and imaging studies to ask questions about how ligand induced signal transduction begins.  Using this approach, the lab has characterized LPS signal transduction, helping to define the TLR4/MD-2 complex as a central LPS recognition molecule. Furthermore, we have identified TLR2 as a central pattern recognition protein for a large variety of important immunostimulatory substances from pyogenic bacteria, fungi, mycoplasma and mycobacteria. We are particularly interested in how receptors change from being inactive to active, and have recently focused on the induced change in conformation and activity of TLR9 after it binds stimulatory DNA.  We believe that such approaches provide us with new insights into the molecular basis of infectious illness, as well as a variety of sterile inflammatory illnesses such as Systemic Lupus Erythematosis and Atherosclerosis, that are mechanistically similar to infectious diseases.  

Representative Publications:

Ingalls, R.R. and D.T. Golenbock. 1995. CD11c/CD18, a transmembrane signaling receptor for lipopolysaccharide. J Exp Med 181:1473-1489.

Delude, R.L., R. Savedra, H. Zhao, R. Thieringer, S. Yamamoto, M.J. Fenton, and D.T. Golenbock. 1995. CD14 enhances cellular responses to endotoxin without imparting ligand-specific recognition. Proc Natl Acad Sci., USA 92: 9288-9292.

A. Yoshimura, Lien, E, Tuomenan, E., Dziarski, R., and D.T. Golenbock. 1999.  Cutting Edge: Recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J. Immunol. 163(1): 1-5.

Schromm, A. B., E. Lien, P. Henneke, J. C. Chow, A. Yoshimura, H. Heine, E. Latz, B. G. Monks, D. A. Schwartz, K. Miyake, and D. T. Golenbock. 2001. Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. J Exp Med 194:79.

Malley, R., Henneke, P., Morse, S.C., Cieslewicz, M.J,, Lipsitch, M., Thompson, C.M., Kurt-Jones, E., Paton, J.C., Wessels, M.R., and D.T. Golenbock.  2003. Recognition Of Pneumolysin By Toll-Like Receptor (TLR) 4 Confers Resistance To Pneumococcal Infection.  Proc Natl Acad Sci USA 18;100(4):1966-1971

Fitzgerald, KA, DC Rowe, BJ Barnes, DR Caffrey, A Visintin, E Latz, B Monks, PM Pitha, and D.T. Golenbock. 2003. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med 198:1043.

Latz, E., A. Schoenemeyer, A. Visintin, K. A. Fitzgerald, B. G. Monks, C. F. Knetter, E. Lien, N. J. Nilsen, T. Espevik, and D. T. Golenbock. 2004. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 5:190.

DC Rowe, A McGettrick, E Latz, BG Monks, NJ Gay, M Yamamoto, S Akira, LAJ O’Neill, KA Fitzgerald and D.T. Golenbock.  2006. The myristoylation of TRIF-Related Adapter Molecule (TRAM) is essential for maximal responses to endotoxin. Proc Natl Acad Sci., USA. 103(16):6299-304.

Peggy Parroche, Fanny N. Lauw, Nadege Goutagny, Eicke Latz, Brian G. Monks, Alberto Visintin, Kristen A. Halmen, Marc Lamphier, Martin Olivier, Daniella C. Bartholomeu, Ricardo T. Gazzinelli, and D. T. Golenbock. 2007.  Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. Proc Natl Acad Sci., USA 104(6):1919-24

Latz E, Verma A, Visintin A, Gong M, Sirois CM, Klein DC, Monks BG, McKnight CJ, Lamphier MS, Duprex WP, Espevik T, and D. T. Golenbock. 2007.  Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol. 2007 Jul;8(7):772-9.

Hampton, R.Y., D.T. Golenbock, M. Penman, M. Krieger and C.R. Raetz. 1991. Recognition and plasma clearance of endotoxin by scavenger receptors. Nature 352: 342.

Golenbock, D.T., R.Y. Hampton, N. Qureshi, K. Takayama and C.R.H. Raetz. 1991. Lipid A-like molecules that antagonize the effects of endotoxins on human monocytes. J Biol Chem 266: 19490.

Golenbock, D.T., Y. Liu, F.H. Millham, M.W. Freeman and R. Zoeller. 1993. Surface Expression of Human CD14 In Chinese Hamster Ovary Fibroblasts Imparts Macrophage-like Responsiveness to Bacterial Endotoxin. J Biol Chem 268: 22055.

Ingalls, R.R. and D.T. Golenbock. 1995. CD11c/CD18, a transmembrane signaling receptor for lipopolysaccharide. J Exp Med 181: 1473-1489.

Delude, R.L., R. Savedra, H. Zhao, R. Thieringer, S. Yamamoto, M.J. Fenton, and D.T. Golenbock. 1995. CD14 enhances cellular responses to endotoxin without imparting ligand-specific recognition. Proc Natl Acad Sci., USA 92: 9288-9292.

Wurfel, M.M., Monks, B., Ingalls, R.R., Dedrick R.L., Delude R, Zhou., Lamping, N, Schumann, R.R., Thieringer, R., Fenton, M.J., Wright S.D., and Golenbock, D.T. 1997. Targeted deletion of the LBP gene leads to profound suppression of LPS responses ex vivo while in vivo responses remain intact. J. Exp. Med. 186 (12): 2151-56.

Delude, R.L., Yoshimura, A., Ingalls, R.R. and D.T. Golenbock. 1998. Construction of an LPS reporter cell line and its use in identifying mutants defective in endotoxin, but not TNF-a, signal transduction. J. Immunol. 161(6): 3001-9.

J.C. Chow, D.W. Young, D.T. Golenbock, W.J. Christ, and F. Gusovsky. 1999. Toll-like Receptor-4 Mediates Lipopolysaccharide-induced Signal Transduction J. Biol. Chem. 1999 274: 10689-10692.

H. H. Heine, C. J. Kirschning, E. Lien, B. G. Monks, M. Rothe, and D. T. Golenbock. 1999. Cutting Edge: Cells That Carry A Null Allele for Toll-Like Receptor 2 Are Capable of Responding to Endotoxin. J Immunol 162: 6971.

A. Yoshimura, Lien, E, Tuomenan, E., Dziarski, R., and D.T. Golenbock. Cutting Edge: Recognition of G-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J. Immunol. 163(1): 1-5.

E. Lien, T.J. Sellati, A. Yoshimura, T.H. Flo, G. Rawadi, R. W. Finberg, J. D. Carroll, T. Espevik, R. R. Ingalls, J. D. Radolf and D.T. Golenbock. 1999. Toll-like receptor 2 functions as a pattern receptor for diverse bacterial cell wall products. J. Biol. Chem. 274: 33419-33425.

E.Lien T.K. Means, H. Heine, A.Yoshimura, S.Kusumoto, K. Fukase, M.J. Fenton, M. Oikawa, N. Qureshi, B.Monks, R.W. Finberg, R.R. Ingalls and D.T. Golenbock. 2000. Toll-like Receptor 4 Imparts Ligand-Specific Recognition of Bacterial Lipopolysaccharide. J. Clin. Invest. 105(4): 497-504.

Golenbock, D. T., and M. J. Fenton. 2001. Extolling the diversity of bacterial endotoxins. Nat Immunol 2: 286.

Schromm, A. B., E. Lien, P. Henneke, J. C. Chow, A. Yoshimura, H. Heine, E. Latz, B. G. Monks, D. A. Schwartz, K. Miyake, and D. T. Golenbock. 2001. Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. J Exp Med 194: 79.

Henneke, P., and D. T. Golenbock. 2001. TIRAP: how Toll receptors fraternize. Nat Immunol 2: 828.

Ingalls RR, Lien E and D.T. Golenbock. 2001. Membrane-associated proteins of a lipopolysaccharide-deficient mutant of Neisseria meningitidis activate the inflammatory response through toll-like receptor 2. Infect Immun 69(4): 2230-6.

Henneke P, Takeuchi O, van Strijp JA, Guttormsen HK, Smith JA, Schromm AB, Espevik TA, Akira S, Nizet V, Kasper DL, and D.T. Golenbock. 2001. Novel engagement of CD14 and multiple toll-like receptors by group B streptococci. J Immunol 167(12):7069-76.

Academic Background

B.S. (1975) University of Michigan
M.D. (1980) University of Michigan

Office: LRB 208
Phone: 508-856-5980
Fax: 508-856-5463
E-mail: Douglas.Golenbock@umassmed.edu

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