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

项目1，摘要 结核分枝杆菌(Mtb)必须适应宿主内的酸性生态位，包括巨噬细胞。 吞噬小体和肉芽肿的干酪层。之前的工作导致了耐酸基因的鉴定， 使结核分枝杆菌能够在严重的酸胁迫下存活下来。实现这一目标的关键途径和基本机制 MTB适应并在中等酸性条件下复制，这是它从一个主机传播到 另一种，是不完全理解的。 这个项目的中心假设是，暴露在酸性pH下会触发结核分枝杆菌的重新编程 向脂肪和脂肪酸分解代谢，促进细胞表面的生长和重塑 脂类。我们建议：(I)从细胞内和细胞外确定脂肪酸和脂肪代谢的重要性 在酸性pH下适应和生长的贮藏物，(Ii)确定酸性pH对结核杆菌细胞膜的影响 组成并确定pH依赖的细胞膜重塑对结核分枝杆菌抗逆性和 (3)确定结核分枝杆菌在酸性环境中适应和生长所需途径的遗传和物理结构 PH值。这些活动直接有助于我们了解结核分枝杆菌生物学中的关键途径的总体计划目标， 特别关注对适应与疾病相关的压力非常重要的复杂途径。

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.