Defining the role of host lipid repertoire in Mycobacterium tuberculosis infection

确定宿主脂质库在结核分枝杆菌感染中的作用

• 批准号: 9245534
• 负责人: Fikadu G. Tafesse
• 金额: $ 19.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245534
• 关键词: Aerosols; Alveolar Macrophages; Autophagocytosis; Autophagosome; Bacillus (bacterium); Bacteria; Biological; Biology; Breathing; CRISPR/Cas technology; Cell Line; Cell membrane; Cell physiology; Cell surface; Cells; Cessation of life; Clinical; Complex; Cytoplasm; Dendritic Cells; Developing Countries; Development; Diagnostic; Disease; Disease Outcome; Energy-Generating Resources; Enzymes; Foamy Macrophage; Genes; Genome; Genus Mycobacterium; Goals; Granuloma; Immune; Immune system; In Vitro; Incidence; Individual; Infection; Integration Host Factors; Invaded; Knock-out; Knowledge; Lateral; Lead; Life Cycle Stages; Lipid Bilayers; Lipids; Mammals; Membrane; Membrane Lipids; Molecular; Morphology; Multi-Drug Resistance; Mycobacterium tuberculosis; Mycolic Acid; Nail plate; Nutrient; Organelles; Organism; Outcome; Pathogenesis; Pathway interactions; Pattern recognition receptor; Phagocytes; Phagocytosis; Population; Predisposition; Process; Production; Protein Sortings; Reporter; Risk Factors; Role; Signal Transduction; Sphingolipids; Technology; Therapeutic; Toll-like receptors; Tuberculosis; Virulent; Work; World Health Organization; antimicrobial; bactericide; burden of illness; cytokine; disease diagnosis; genome editing; improved; killings; lipid biosynthesis; lipid metabolism; macrophage; microbicide; mutant; new therapeutic target; novel therapeutics; pathogen; physical property; resistant strain; response; success

PROJECT SUMMARY/ABSTRACT Nearly one-third of the world population is infected with Mycobacterium tuberculosis. This reservoir contributes towards an increasing incidence of tuberculosis, with about 11 million new cases and 1.8 million deaths every year. The emergence of multi-drug resistant strains combined with low diagnostic and therapeutic coverage in many developing countries, has worsened the disease burden caused by TB. The profound success of Mycobacterium tuberculosis in causing disease depends on its ability to successfully utilize the host’s cellular machineries including the lipid biosynthesis pathway to subvert the immune system. Our understanding of these processes especially that of the host lipid biology in the context of Mycobacterium tuberculosis infection is limited. The aim of the proposed work is to study the role of host’s lipid biosynthesis in the entry, replication and killing of Mycobacterium tuberculosis. For this purpose, individual knockout macrophage cell lines that lack genes involved in the biosynthesis of lipids will be generated using CRISPR/Cas9-technology. Understanding these pathways or processes essential for the life cycle of Mycobacterium tuberculosis is crucial, as they represent potential targets for new therapeutics.

项目总结/摘要 近三分之一的世界人口感染结核分枝杆菌。这个水库 结核病发病率不断上升，每年约有1100万新病例和180万人死亡。 年多药耐药菌株的出现，加上低诊断和治疗覆盖率， 在许多发展中国家，结核病加重了疾病负担。的巨大成功 结核分枝杆菌在致病过程中依赖于其成功利用宿主细胞的能力， 包括脂质生物合成途径在内的破坏免疫系统的机制。我们理解 这些过程，特别是结核分枝杆菌感染背景下宿主脂质生物学的过程 是有限的。本工作的目的是研究宿主的脂质生物合成在进入、复制中的作用 和杀死结核分枝杆菌。为此目的，单个敲除巨噬细胞细胞系缺乏 参与脂质生物合成的基因将使用CRISPR/Cas9技术产生。理解 这些途径或过程对结核分枝杆菌的生命周期至关重要，因为它们 代表了新疗法的潜在靶点。