New tools for studying M. abscessus pathogenesis

 描述(由申请人提供)：脓肿分枝杆菌是快速生长的非结核分枝杆菌(NTM)物种中的一种新的病原体。脓肿分枝杆菌可引起伤口和皮下感染，但最严重的感染是肺部感染，通常见于有潜在肺部病变的具有免疫能力的老年人，或身材高大、体重较低的老年妇女。值得注意的是，脓肿分枝杆菌也是囊性纤维化患者或接受抗肿瘤坏死因子α(肿瘤坏死因子)治疗的患者的严重肺部疾病的原因。脓肿分枝杆菌属于一个分类学上有争议的类群“感觉分枝杆菌”，其中包括马西里氏分枝杆菌和伯氏分枝杆菌。最近的分析表明，这三种生物是“脓肿”物种名称中不同的亚种。在本提案中，我们将重点介绍脓肿分枝杆菌，也称为脓肿分枝杆菌亚种。脓肿。脓肿分支杆菌成为人类疾病中一种重要的NTM的原因尚不清楚，因为与其他致病分支杆菌相比，脓肿分支杆菌的研究还不够深入。然而，一些研究表明，形态转换可能在脓肿分枝杆菌肺部发病机制中发挥作用。环境中的脓肿分支杆菌分离株通常形成光滑的菌落，而来自深部组织感染患者的分离株形成粗糙的菌落。粗糙表型的出现是细胞膜外层小叶上与糖肽脂(GPL)合成或运输有关的基因突变的结果。光滑细菌是GPL+，形成生物膜，被巨噬细胞吞噬后可以被杀死。相比之下，粗糙的GPL细菌不会形成生物膜，并且对巨噬细胞内的杀戮具有抵抗力。据推测，光滑的形态更适合在环境生态位中生存和宿主的初始定植，而粗糙的形态在宿主组织中具有更深的生存优势。在这一应用中，我们建议在这一假说的框架内开发新的工具来检查肺部疾病中脓肿分枝杆菌的发病机制。

 DESCRIPTION (provided by applicant): Mycobacterium abscessus is an emerging pathogen within the rapidly growing, non-tubercular mycobacterial (NTM) species. M. abscessus can cause wound and subcutaneous infections, but the most serious infections are pulmonary, and usually seen in elderly, immunocompetent individuals with underlying lung pathologies, or tall, elderly women with low body mass. Remarkably, M. abscessus is also responsible for serious pulmonary disease in patients with cystic fibrosis or those undergoing anti-TNFα (tumor necrosis factor) therapy. M. abscessus belongs to a taxonomically contentious group "M. abscessus sensu lato", which includes the pathogens M. massiliense and M. bolletii. Recent analysis has suggested that these three organisms are distinct subspecies within the "abscessus" species designation. For the purpose of this proposal, we will focus on M. abscessus senso stricto, otherwise known as M. abscessus subsp. abscessus. The reasons why M. abscessus has become an important NTM in human disease are not clear because M. abscessus is understudied compared to other pathogenic mycobacteria. However, several studies suggest that a morphological switch may play a role in M. abscessus pulmonary pathogenesis. Environmental isolates of M. abscessus typically form smooth colonies, while isolates from patients with deep tissue infections form rough colonies. The emergence of the rough phenotype results from mutation of genes involved with the synthesis or transport of a glycopeptidolipid (GPL) present on the outer leaflet of the cell envelope. Smooth bacteria are GPL+, form biolfilms, and can be killed after engulfment by macrophages. In contrast, the rough, GPL- bacteria do not form biofilms, and are resistant to killing within macrophages. It is hypothesized that the smooth morphotype is better suited for survival in environmental niches and for the initial colonization of the host, while the rough morphotype has a survival advantage deeper in host tissue. In this application, we propose to develop new tools to examine M. abscessus pathogenesis in pulmonary disease within the framework of this hypothesis.