Clinical Investigation of Host Defense
Innate Immune Response
Michael B. Fessler, M.D.
Deputy Chief, Immunity, Inflammation, and Disease Laboratory and Principal Investigator
Michael B. Fessler, M.D., is Deputy Chief of the Immunity, Inflammation, and Disease Laboratory, heads the Clinical Investigation of Host Defense Group, and holds a secondary appointment in the NIEHS Clinical Research Branch. His group investigates the role of cholesterol trafficking and lipid rafts in innate immunity, and uses proteomic and translational approaches to discover and validate novel insights into the innate immune response.
The group uses genetically modified mouse models, lipid raft analysis and signal transduction approaches to define how cholesterol trafficking mechanisms regulate the innate immune response. The research focuses on defining mechanisms of lung inflammation and host defense along with signaling responses of the leukocyte to lipopolysaccharide and related stimuli. A related but independent effort of the laboratory is protein-protein interaction discovery in innate immunity signaling using targeted applications of proteomics. The group will test and validate the results using human specimens obtained in the NIEHS Clinical Research Unit.
A number of recent reports suggest that innate immunity and host lipid metabolism are integrated. TLR4 responds to both microbial lipids (lipopolysaccharide [LPS]) and host lipids (fatty acids, ceramide, mmLDL), and is thought to initiate its cascade from cholesterol-enriched microdomains of the plasma membrane, lipid rafts. Our observations and others have led to two reciprocal areas of investigation: 1) the role of endogenous regulators of cholesterol/membrane trafficking in initiation and regulation of TLR signaling; and 2) the regulatory influence of innate immunity in host cholesterol metabolism.
In ongoing and future studies, the Environmental Innate Immunity Group will translate its hypotheses and experimental observations to human disease through studies in the NIEHS Clinical Research Unit.
Major areas of research:
- Roles of raft remodeling in induction and regulation of the innate immune response
- Role of cholesterol trafficking regulators in innate immunity
- Mechanisms of lung inflammation and host defense
- Protein-protein interaction and post-translational modification discovery in innate immunity
- Using RNA interference and selected genetically modified mice to identify regulatory roles for cholesterol trafficking in the innate immune response in leukocytes.
- Employing targeted proteomic strategies to identify novel events and molecular targets in the lipopolysaccharide signaling pathway.
- Testing genetically modified mice to define mechanisms underlying acute pulmonary inflammation, pulmonary host defense, and pulmonary fibrosis.
Fessler received a B.A. in philosophy from Princeton University in 1992, a medical degree from Harvard Medical School in 1996 and training in Internal Medicine at Massachusetts General Hospital from 1996-1999 and in Pulmonary/Critical Care Medicine at the University of Colorado from 1999-2002. Fessler developed an expertise in basic and translational approaches to the study of innate immunity, which he expanded during four years of a faculty position at the University of Colorado, before joining the NIEHS in 2006.