Alternative Respiratory Chains of M. tuberculosis

描述(申请人提供)：世界上约三分之一的人口感染结核分枝杆菌。在临床潜伏期内可能持续数十年的对峙中，结核分枝杆菌种群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下降而降低。然后细菌复制可以恢复，潜伏性病灶的重新激活导致约10%的具有免疫能力的结核分枝杆菌感染者临床疾病。活动性肺结核的药物治疗需要6至9个月。过早终止治疗降低了治疗成功率，并导致耐药和多药耐药结核分枝杆菌的发展和蔓延。治疗活动性结核病的药物对感染潜伏期的结核分枝杆菌和非复制型结核分枝杆菌相对无效。对非复制型结核分枝杆菌有效的新药可能会缩短活动性结核病的药物治疗，并允许治疗潜伏感染的人，这些人有发展成活动性结核病的高风险。呼吸是大多数细菌生长的基础，也是在抑菌过程中生存的基础。在结核杆菌中存在但在人类中不存在的呼吸链可能是开发新的抗分枝杆菌药物的合适靶点，这些药物对持续生长的细菌具有活性。该项目的目标是确定这些(替代)呼吸链对结核分枝杆菌发病的重要性。我们将通过监测呼吸酶编码基因的表达水平的实验来确定结核杆菌的能量代谢如何适应宿主内遇到的环境。利用转座子突变体，我们将测试替代呼吸链是否对小鼠结核杆菌的发病起重要作用。我们还将调查具有低生物能量效率的呼吸链是否对病原体代谢脂肪酸等高度还原的碳源的能力重要，以及无氧呼吸是否对结核分枝杆菌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.