Dr. Douglas Golenbock is Chief of the Division of Infectious Diseases and Immunology in the Department of Medicine at UMass. He holds a joint appointment in the Department of Microbiology and Physiological Systems. The principal goal of his laboratory is to characterize the receptors used by phagocytes to respond to the presence of microbes. The lab works on several important infectious illnesses. Furthermore, as the mechanisms of inflammation observed in infectious diseases are similar in nature to those associated with sterile inflammation, they also study Alzheimer’s disease. Much of their malaria work is done in the Amazonian city of Porto Velho, Brazil. Virtually all of the work in the lab focuses on two groups of innate immune receptors: Toll-like receptors (TLRs) and Nod-like receptors (NLRs). Their entry into the TLR field was heralded by the discovery that TLR4, and its co receptor MD-2, mediate responses to bacterial endotoxin, a major cause of septic shock. More recently, they have begun to focus on intracellular nucleic acid receptors both as regulators of IL-1b production and type I interferons.
There are six major projects in his laboratory:
1. Defining the response to bacterial lipopolysaccharide (LPS, endotoxin). LPS is the major glycolipid present 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, as well as adapter molecules that transduce an activation signal in response to LPS. 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 Drs. Peter Rice (program PI), Sanjay Ram and Dr. Golenbock.
3. Defining the innate immune response to P. falciparum malaria. Very little is known about how P. falciparum causes inflammation. His lab has 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. His lab has 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: Pyogenic Arthritis, Pyoderma gangrenosum and Acne. The disease is due to dysregulation of IL-1b 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 Alzheimer’s disease. Alzheimer’s disease is a chronic inflammatory disease that causes dementia and death. It is caused, in part, by the accumulation of beta amyloid, an insoluble peptide derived from amyloid precursor 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. In order to accomplish these goals, the Division has organized the “Toll meetings”, a series of innate immunity meetings in which the Division partners with a foreign institution to provide participants with an update on the most important advances in innate immunity. They have now had four Toll meetings: Toll2004 (Taormina, Italy), Toll2006 (Salvador, Brazil), Toll2008 (Cascais, Portugal) and Toll2011 (Riva del Garda, Italy). Virtually all of their research faculty, students and post-docs attend the Toll meetings.