Alternative Respiratory Chains of M. tuberculosis

描述（由申请人提供）：世界上约三分之一的人口感染结核分枝杆菌（MTB）。在临床潜伏期期间可能持续数十年的对峙中，MTB群体持续处于明显的抑菌状态，直到宿主限制病原体生长的能力因细胞介导的免疫力下降而降低。然后细菌复制可以恢复，并且潜伏病灶的再活化导致约10%的感染MTB的免疫活性个体的临床疾病。活动性结核病的药物治疗需要6至9个月。过早终止治疗会降低治疗的成功率，并导致耐药和多药耐药结核病的发展和传播。用于治疗活动性TB的药物对感染潜伏期的MTB和非复制型MTB相对无效。对非复制型结核分枝杆菌有活性的新药可能会缩短活动性结核病的药物治疗时间，并允许治疗潜伏感染者，这些人有发展为活动性结核病的高风险。呼吸是大多数细菌物种生长的基础，也是抑菌期间存活的基础。在MTB中出现但在人类中不存在的呼吸链可能是开发新型抗分枝杆菌药物的合适靶点，这些药物对持续存在和生长的细菌具有活性。该项目的目标是确定这些（替代）呼吸链对MTB发病机制的重要性。我们将通过监测编码呼吸酶的基因表达水平的实验来确定MTB的能量代谢如何适应宿主内遇到的环境。使用转座子突变体，我们将测试是否替代呼吸链是重要的MTB在小鼠中的发病机制。我们还将研究具有低生物能效率的呼吸链是否对病原体代谢高度还原的碳源如脂肪酸的能力很重要，以及无氧呼吸是否对MTB在缺氧中生存至关重要。

DESCRIPTION (provided by applicant): About a third of the world's population is infected with Mycobacterium tuberculosis (MTB). In a stand off that may last decades during the period of clinical latency, a population of MTB persists in a state of apparent bacteriostasis until the host's ability to restrict growth of the pathogen is reduced by declining cell-mediated immunity. Then bacterial replication can resume and reactivation of latent foci leads to clinical disease in about 10% of the immune-competent individuals infected with MTB. Drug therapy of active TB takes 6 to 9 months. Premature termination of therapy decreases its success rate and leads to the development and spread of drug resistant and multi-drug resistant MTB. Drugs for treating active TB are relatively ineffective against MTB in the latent phase of the infection and against non-replicating MTB. New drugs that are active against non-replicating MTB might shorten drug therapy of active TB and also allow the treatment of latently infected individuals that are at high risk to develop active TB. Respiration is fundamental for growth of most bacterial species and also for survival during bacteriostasis. Respiratory chains that occur in MTB but not in humans might be suitable targets for the development of novel anti-mycobacterial drugs that are active against persisting as well as growing bacteria. The goal of this project is to determine the importance of these (alternative) respiratory chains for MTB pathogenesis. We will determine how the energy metabolism of MTB adapts to environments encountered within the host with experiments that monitor the expression levels of genes encoding respiratory enzymes. Using transposon mutants we will test whether alternative respiratory chains are important for pathogenesis of MTB in mice. We will also investigate whether respiratory chains with a low bioenergetic efficiency are important for the pathogen's ability to metabolize highly reduced carbon sources like fatty acids and whether anaerobic respiration is essential for MTB to survive hypoxia.