New tools for studying M. abscessus pathogenesis

研究脓肿分枝杆菌发病机制的新工具

• 批准号: 9107388
• 负责人: Martin S. Pavelka
• 金额: $ 15.35万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-07 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107388
• 关键词: Bacteria; Biology; Development; Elderly; Elderly woman; Gene Mutation; Genus Mycobacterium; Goals; Human; Immunocompetent; Immunocompromised Host; Individual; Infection; Interferons; Knock-out; Lung; Lung diseases; Methodology; Methods; Microbial Biofilms; Modeling; Mus; Mutagenesis; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Operative Surgical Procedures; Organism; Pathogenesis; Patients; Phenotype; Play; Prevention; Pulmonary Pathology; Research; Research Project Grants; Resistance; Role; Site-Directed Mutagenesis; TNF gene; Tissues; Treatment Protocols; Tumor Necrosis Factor Therapy; United States National Institutes of Health; Work; cell envelope; cystic fibrosis patients; design; genetic manipulation; human disease; improved; in vivo; killings; macrophage; mouse model; mutant; mycobacterial; novel; pathogen; programs; public health relevance; research study; subcutaneous; tool; wound

 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.

 描述（由申请方提供）：结核分枝杆菌是快速生长的非结核分枝杆菌（NTM）种属中的一种新兴病原体。M.脓毒症可引起伤口和皮下感染，但最严重的感染是肺部感染，通常见于具有潜在肺部病变的免疫功能正常的老年人，或体重较低的高大老年女性。值得注意的是，M。在囊性纤维化患者或接受抗TNF α（肿瘤坏死因子）治疗的患者中，肺纤维化也是导致严重肺部疾病的原因。M. Mesquessus属于一个分类学上有争议的组“M。广义上的”寄生虫“，包括病原体M. massiliense和M.博莱蒂。最近的分析表明，这三种生物是“虫”物种名称中的不同亚种。为了这个建议的目的，我们将集中在M。严格意义上的刺蛾，也称为M.红腹叶蝉亚种你好M.由于M.与其他致病性分枝杆菌相比，分枝杆菌的研究不足。然而，一些研究表明，形态开关可能在M。肺水肿的发病机制。环境分离物M.大肠杆菌通常形成光滑的菌落，而从深部组织感染患者分离的菌株形成粗糙的菌落。粗糙表型的出现是由参与细胞包膜外叶糖肽脂（GPL）合成或转运的基因突变引起的。光滑细菌是GPL+，形成生物膜，并且可以在被巨噬细胞吞噬后被杀死。相比之下，粗糙的GPL-细菌不形成生物膜，并且对巨噬细胞内的杀伤具有抗性。据推测，光滑形态型更适合在环境小生境中生存和宿主的初始定殖，而粗糙形态型在宿主组织更深处具有生存优势。在这个应用中，我们建议开发新的工具来检查M。在这一假说的框架内，肺疾病的发病机制。