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: 8814644
• 负责人: Martin S. Pavelka
• 金额: $ 27.35万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8814644
• 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; Pathology; Patients; Phenotype; Play; Prevention; Research; Research Project Grants; Resistance; Role; Site-Directed Mutagenesis; TNF gene; Tissues; Treatment Protocols; Tumor Necrosis Factor Therapy; Tumor Necrosis Factor-alpha; 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) 物种中的一种新兴病原体。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，通常见于患有潜在肺部病变的免疫功能健全的老年人，或身材高大、体重较低的老年女性。值得注意的是，脓肿分枝杆菌还导致囊性纤维化患者或接受抗 TNFα（肿瘤坏死因子）治疗的患者出现严重肺部疾病。脓肿分枝杆菌属于分类学上有争议的群体“脓肿分枝杆菌”，其中包括病原体马斯利分枝杆菌和博氏分枝杆菌。最近的分析表明，这三种生物体是“脓肿”物种名称中的不同亚种。出于本提案的目的，我们将重点关注严格脓肿分枝杆菌，也称为脓肿分枝杆菌亚种。脓肿。脓肿分枝杆菌成为人类疾病中重要的 NTM 的原因尚不清楚，因为与其他致病分枝杆菌相比，脓肿分枝杆菌的研究还不够充分。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。脓肿分枝杆菌的环境分离物通常形成光滑的菌落，而来自深部组织感染患者的分离物则形成粗糙的菌落。粗糙表型的出现是由于与细胞膜外叶上存在的糖肽脂 (GPL) 的合成或运输有关的基因突变所致。光滑细菌为GPL+，形成生物膜，被巨噬细胞吞噬后可被杀死。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伤具有抵抗力。据推测，光滑形态型更适合在环境生态位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。在此应用中，我们建议开发新工具来在该假设的框架内检查肺部疾病中脓肿分枝杆菌的发病机制。