Academic Background

Innate immunity and Infectious Diseases.

Dr. Douglas Golenbock is Chief of the Division of Infectious Diseases and Immunology in the Department of Medicine. He holds a joint appointment in the Department of Microbiology and Physiological Systems. The goal of his laboratory is to characterize phagocytic receptors that recognize the presence of microbes in the context of infectious illnesses. As the mechanisms of inflammation in infectious diseases are similar to those associated with sterile inflammation, we also study Alzheimer's Disease.    Virtually all of our work focuses on two groups of receptors: Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in the context of the inflammasome.

 Our entry into the TLR field was heralded by the discovery that TLR4, and MD-2 mediate responses to bacterial endotoxin, a major cause of sepsis. More recently, we have begun to focus on intracellular nucleic acid receptors as regulators of IL-1 production and type I interferons. There are six major projects in the laboratory:

1. Defining the response to bacterial lipopolysaccharide (LPS, endotoxin). LPS immunologically potent amphipathic glycolipid on the surface of Gram-negative bacteria. It is thought to be responsible for Gram-negative sepsis. This project involves detailed studies of TLR4/MD-2 and adapter molecules that transduce an activation signal. The work is funded via an NIH merit award to Dr. Golenbock.

2. Characterizing the role of the LPS receptor system, in pelvic inflammatory disease. This project is based upon the realization that Neisseria gonorrhoeae mediates much of its inflammation via the TLR4/MD-2 signaling pathway and is funded via an NIH U19 award that includes other infectious diseases faculty, including Drs. Peter Rice (program PI) and Sanjay Ram.

3. Defining the innate immune response to P. falciparum malaria. Very little is known about how P. falciparum causes inflammation. We have developed several projects in this area, including basic investigations into nucleic acid receptors and inflammasomes. This is a large project that is a collaboration with two other UMass investigators, Drs. Kate Fitzgerald and Ricardo Gazzinelli. The project is funded via an RO1 to Drs. Golenbock and Fitzgerald.

4. Defining the innate immune response to Group B streptococcus. We have previously demonstrated that Group B streptococcus activates type I interferon production as a result of hemolysin expression, which allows DNA access to the phagocyte cytosolic compartment. Recent studies also implicate hemolysin as a mediator of NLRP3 activation via the effects of bacterial RNA. This project is a three way collaboration with a bacterial genetics group at the Institut Pasteur (France) headed by Dr. Patrick Trieu-Cuot and a cell biology group at the University of Freiburg (Germany) run by Dr. Philipp Henneke, a former Golenbock post-doctoral fellow, and is funded by an RO1 grant to Dr. Golenbock.

5. Defining a role for PSTPIP1. PSTPIP1 is a protein that causes an autoinflammatory disorder known as PAPA syndrome: Pogenic Arthritis, Pyoderma gangrenosum and Acne. The disease is due to dysregulation of IL-1 production that probably results from the activation on pyrin, the gene product associated with Familial Mediterranean Fever. Dr. Donghai Wang, a member of the Golenbock laboratory, has engineered mice that are either deficient in PSTPIP1, or that carry the known lesions of PAPA syndrome. It is funded by an R21 grant to Drs. Wang and Golenbock.

6. Examining the role of the NLRP3 inflammasome in Alzheimers Disease. Alzheimer (AD) is a chronic inflammatory disease that causes premature dementia and death. It appears to be caused, in part, by -amyloid, an insoluble protein that activates the NLRP3 inflammasome in microglial cells, resulting in neuronal cell death.

One of the major goals of the Golenbock lab and the Division of Infectious Diseases is to promote UMass immunology and the field of innate immunity in general. The Division has organized the state of the art meetng in the field of innate immunity. We have now had four Toll meetings: Toll2004 (Taormina, Italy), Toll2006 (Salvador, Brazil; www.toll2006.org), Toll2008 (Cascais, Portugal; www.toll2008.org) and Toll2011 (Riva del Garda, Italy; www.toll2011.org). Virtually all of the research faculty, students and post-docs in Infectious Diseases attend the Toll meetings, which typically involve ~ 600 participants.

For More information on Toll related meetings please see

 http://www.youtube.com/watch?v=2rqQOmkiL5o

For More information on Targeting a new therapy for Alzheimer's pleas see:

 http://www.youtube.com/watch?v=5LXshrNFkXA