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，可引起伤口和皮下感染，但最严重的感染是肺部感染，通常见于老年人。 、患有潜在肺部疾病的免疫功能正常的个体，或体重较低的高个子老年女性。值得注意的是，脓肿分枝杆菌也是囊性患者严重肺部疾病的原因。纤维化或接受抗 TNFα（肿瘤坏死因子）治疗的脓肿分枝杆菌属于分类学上有争议的“脓肿分枝杆菌”，其中包括病原体 M. Massiliense 和 M. bolletii。脓肿菌是“脓肿”物种名称中的不同亚种。出于本提案的目的，我们将重点关注脓肿脓肿菌，也称为“脓肿菌”。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，脓肿分枝杆菌尚未得到充分研究。脓肿分枝杆菌肺部发病机制。脓肿分枝杆菌的环境分离株通常形成光滑菌落，而来自深层感染组织的分离株则形成粗糙菌落。粗糙表型的出现是由于相关基因突变造成的。光滑细菌是 GPL+，可在被巨噬细胞吞噬后被杀死，而粗糙的 GPL- 细菌则不会形成。人们重新认识到，光滑形态更适合在环境生态位中生存和宿主的初始定殖，而粗糙形态则更适合宿主的初始定植。形态型在宿主组织中具有更深的生存优势，我们建议在这一假设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。