Integration of host lipid metabolism and innate immunity in microbial infection

项目概述：本项目的目的是深入了解宿主脂蛋白和磷脂代谢影响分枝杆菌感染免疫反应的机制。初步数据表明，麻风病病变和体外感染的巨噬细胞积累宿主来源的氧化磷脂，抑制先天免疫。值得注意的是，正常的高密度脂蛋白（HDL），一种氧化磷脂的清道夫和逆向脂质转运的介质，可以在分枝杆菌感染期间保持先天免疫反应。本研究旨在：1)验证不同巨噬细胞亚群介导麻风病进展型中氧化脂蛋白摄取的假设；2)确定脂质积累对先天免疫反应和分枝杆菌生长的影响；3)确定诱导脂质逆向转运的药物是否可以保护先天免疫反应并限制分枝杆菌生长。重要的是，这项工作代表了一种新的治疗分枝杆菌病原体的策略。候选人和环境：首席研究员是一位心脏病学和免疫学博士学位的助理教授。他所受的广泛培训使他能够构思和综合这一提案，该提案涵盖了先天免疫、传染病和脂蛋白代谢领域：候选人将在加州大学洛杉矶分校世界知名免疫学家罗伯特·莫德林的指导下进行。目标和职业发展：近期目标将是探索宿主脂质代谢和先天免疫在微生物感染中的整合，以麻风病为模型。长期目标是利用这一经验成为一名成熟的研究者，将这些免疫原理应用于慢性炎症性疾病，如动脉粥样硬化。摘要：分枝杆菌部分通过逃避宿主免疫导致发病和死亡。本研究探讨了宿主脂质氧化如何在抑制宿主免疫防御中发挥重要作用，并将探索通过恢复脂质同质性来恢复宿主免疫应答的新策略。相关性（见说明）：对麻风病的研究有助于建立免疫范式，包括1型和2型免疫以及Toll样受体在微生物感染中的功能。通过本提案的工作，我们将定义在慢性炎症中具有不同表型和功能的关键巨噬细胞亚群-我们相信这些发现将直接适用于其他更普遍的疾病，如动脉粥样硬化。（摘要结束）

DESCRIPTION (provided by applicant): PROJECT SUMMARY: 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. RELEVANCE (See instructions): 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. (End of Abstract)