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New tools for studying M. abscessus pathogenesis

研究脓肿分枝杆菌发病机制的新工具

基本信息

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
项目类别：
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

项目摘要

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.