The Role of Atypical Cell Wall Biology of Mycobacterium abscessus in Pulmonary Infection and Therapy

项目摘要 患有结构性肺部疾病的患者，如囊性纤维化和支气管扩张， 结核分枝杆菌感染。这些病原体可在约13%的囊性纤维化患者的痰液中检出 美国的病人。除了那些有潜在的肺部疾病，免疫能力强的绝经后妇女， 白人女性也选择性地易患肺M。尿道感染。尽管越来越多 尽管该病的流行率很高，但对M.你好 这项建议的目的是填补我们对肺M的理解的关键空白。尿道感染。最近 研究表明，M.塞苏斯群岛 与其他革兰氏阴性和革兰氏阳性细菌相比，其合成的最后一步是独特的。此外，委员会认为， 这种区别是由于非经典转肽酶的活性。我会研究这些小说的相关性 转肽酶对M.大肠杆菌肽聚糖及其在急性和慢性炎症中的作用 肺部感染的阶段。调查M。体内的排泄物是至关重要的，但是目前已发表的报告 的小鼠模型往往缺乏持续的慢性感染，类似于囊性纤维化或 支气管扩张患者。它们也缺乏明显的病理进展。我开发了一个小鼠模型 它满足这两个标准，不仅产生慢性M。肺部感染，但也 导致与在人类中观察到的相似的大体病理学发现。 本提案中概述的研究将为M.菌丝细胞壁代谢 以及感染过程中的生理学，这可能会导致新的治疗发展和新的化疗 现有的抗生素。

PROJECT SUMMARY Patients with structural lung conditions, such as cystic fibrosis and bronchiectasis are highly susceptible to infections with Mycobacterium abscessus. These pathogens are detected in the sputum of ~13% of cystic fibrosis patients in the US. In addition to those with underlying lung conditions, immune competent post-menopausal Caucasian women are also selectively susceptible to pulmonary M. abscessus infections. Despite increasing prevalence of this disease, very little is known about the pathogenesis of pulmonary infections with M. abscessus. This proposal’s aim is to fill critical gaps in our understanding of pulmonary M. abscessus infection. Recent studies have demonstrated that the peptidoglycan, the exoskeleton of the bacterial cell, of M. abscessus is unique in the final step of its synthesis compared to other gram negative and gram positive bacteria. Furthermore, this distinction is due to the activities of non-classical transpeptidases. I will study the relevance of these novel transpeptidases to the physiology of M. abscessus peptidoglycan and their contribution during acute and chronic stages of pulmonary infection. Investigating M. abscessus in vivo is critical, however current published accounts of mouse models often lack a sustained chronic infection analogous to what would occur in cystic fibrosis or bronchiectasis patients. They also lack demonstrated progression to pathology. I have developed a mouse model which fulfills both of these criteria, generating not only a chronic M. abscessus pulmonary infection, but also leading to gross pathological findings that mimic those observed in humans. The studies outlined in this proposal will provide new insights into aspects of M. abscessus cell wall metabolism and physiology during infection that could lead to novel therapeutic development and novel chemotherapy regimens of existing antibiotics.