The objective of this proposal is to gain insight into the mechanisms by which host lipoprotein and phospholipid metabolism influence the immunologic response to mycobacterial infection. Preliminary data demonstrate that infected macrophages in leprosy lesions and in vitro accumulate host- derived oxidized phospholipids that inhibit innate immunity. Remarkably, normal high density lipoprotein (HDL), a scavenger of oxidized phospholipids and mediator of reverse lipid transport can preserve innate immune responses during mycobacterial infection. This proposal aims to: 1) test the hypothesis that distinct macrophage subsets mediate uptake of oxidized lipoproteins in the progressive form of leprosy, 2) determine the effects of lipid accumulation on innate immune responses and mycobacterial growth, and 3) determine if agents that induce reverse lipid transport can preserve innate immune responses and restrict mycobacterial growth. Importantly, this work represents a novel therapeutic strategy against mycobacterial pathogens. CANDIDATE AND ENVIRONMENT: The principal investigator is an Assistant Professor with doctoral training in both cardiology and immunology. The breadth of his training allowed for the conception and synthesis of this proposal, which spans the fields of innate immunity, infectious disease, and lipoprotein metabolism: The candidate will be under the mentorship of Robert Modlin, a world-renowned immunologlst at UCLA. GOALS AND CAREER DEVELOPMENT: The immediate goal will be to explore the integration of host lipid metabolism and innate immunity in microbial infection, using leprosy as a model. The long term goal will be to use this experience to become an established investigator that can apply these immunogic principles to " chronic inflammatory diseases, such as atherosclerosis. LAY SUMMARY: Mycobacteria cause morbidity and mortality in part by evading host immunity. This proposal explores how oxidation of host lipids plays an important role in inhibiting host immune defenses, and will explore novel strategies to regain host immune responses by restoring lipid homeosatis.
Studies in leprosy have helped establish immunologic paradigms, including type 1 and type 2 immunity and the funciton of Toll like receptors in microbial infection. Through the work in this proposal, we will define key macrophage subsets that possess divergent phenotype and function in chronic inflammation- findings that we believe that will be directly applicable to other more prevalent diseases, such as atherosclerosis.
|Cruz, Daniel; Wang, Zhiming; Kibbie, Jon et al. (2011) Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity. Proc Natl Acad Sci U S A 108:6769-74|