Project 1. Metabolic adaptations required for growth and virulence of Mtb at acidic pH.

项目 1. Mtb 在酸性 pH 条件下生长和毒力所需的代谢适应。

• 批准号: 10190813
• 负责人: SABINE EHRT
• 金额: $ 30.05万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-12 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10190813
• 关键词: Acids; Anabolism; Antibiotic Therapy; Automobile Driving; Biochemical; Biology; Carbon; Catabolism; Cell surface; Cells; Collaborations; Complex; Data; Defect; Disease; Dyes; Enzyme Interaction; Enzymes; Exposure to; Fatty Acids; Gene Expression Profiling; Genes; Genetic; Goals; Granuloma; Growth; Immune response; Immunoprecipitation; In Vitro; Infection; Insertional Mutagenesis; Label; Lipids; M. tuberculosis genome; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Pathway; Metabolism; Multienzyme Complexes; Mycobacterium tuberculosis; Nature; Nutritional; Pathogenesis; Pathway Analysis; Pathway interactions; Phagosomes; Phase; Property; Proteins; Regulation; Resistance; Signal Transduction; Source; Stains; Stress; Structure; Testing; Tuberculosis; Virulence; Work; acid stress; base; cell envelope; enzyme pathway; experimental study; extracellular; fatty acid metabolism; gene induction; lipid biosynthesis; lipid metabolism; macrophage; mutant; next generation sequencing; novel; programs; resistance gene; transcriptome sequencing; transposon sequencing

Project 1, Abstract Mycobacterium tuberculosis (Mtb) has to adapt to acidic niches inside the host, which include macrophages phagosomes and the caseum of granulomas. Previous work led to the identification of acid resistance genes, that enable Mtb to survive severe acid stress. The key pathways and underlying mechanisms that that enable Mtb to adapt to and replicate in mildly acidic conditions, a requirement for its ability to transmit from one host to another, are incompletely understood. The central hypothesis driving this project is that exposure to acidic pH triggers a reprogramming of Mtb’s metabolism towards lipid and fatty acid catabolism which facilitates growth and remodeling of its cell surface lipids. We propose to (i) determine the importance of fatty acid and lipid metabolism from intra- and extracellular stores for adaptation to and growth at acidic pH, (ii) determine the impact of acid pH on Mtb’s cell envelope composition and define the importance of pH-dependent cell envelope remodeling for Mtb stress resistance and (iii) define the genetic and physical structure of pathways required for Mtb’s adaptation to and growth at acidic pH. These activities directly contribute to our overall program goal to understand key pathways in Mtb biology, with a particular focus on complex pathways that are important for the adaptation to disease-relevant stress.

项目1，摘要 结核分枝杆菌（Mtb）必须适应宿主体内的酸性环境，其中包括巨噬细胞 吞噬体和肉芽肿的干酪。以前的工作导致了抗酸基因的鉴定， 使结核分枝杆菌能够在严重的酸胁迫下存活。关键的途径和潜在的机制， 结核杆菌适应并在温和的酸性条件下复制，这是其从一个宿主传播到另一个宿主的能力的必要条件。 另一个，还没有完全理解。 推动这一项目的中心假设是，暴露于酸性pH值会触发结核分枝杆菌的重新编程， 向脂质和脂肪酸催化剂代谢，促进其细胞表面的生长和重塑 脂质。我们建议（i）从细胞内和细胞外确定脂肪酸和脂质代谢的重要性 用于适应酸性pH和在酸性pH下生长的储存，（ii）确定酸性pH对Mtb的细胞包膜的影响 组合物，并定义了pH依赖性细胞包膜重塑对Mtb应激抗性的重要性， (iii)确定结核分枝杆菌适应和生长在酸性环境所需的遗传和物理结构 博士这些活动直接有助于我们的整体计划目标，了解结核病生物学的关键途径， 特别关注对适应疾病相关压力至关重要的复杂途径。