Genetic and Functional Traits of Cultivated Nasal Bacteria in Relapsing Granulomatosis with Polyangiitis

复发性肉芽肿性多血管炎鼻腔培养细菌的遗传和功能特征

• 批准号: 10045315
• 负责人: Rennie Rhee
• 金额: $ 10.22万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045315
• 关键词: 16S ribosomal RNA sequencing; Affect; Autoimmune Responses; Autoimmunity; Bacteria; Clinical; Collaborations; Corynebacterium; DNA; DNA sequencing; Data; Detection; Development; Disease; Enrollment; Epithelial Cells; Flare; Freezing; Future; Genes; Genetic; Genus staphylococcus; Granulomatous; Growth; Heterogeneity; High-Throughput Nucleotide Sequencing; Human; Immunity; In Vitro; Inflammation; Investigation; K-Series Research Career Programs; Knowledge; Lead; Longitudinal Studies; Mediating; Metabolic; Methods; Microbe; Microbial Genetics; Mucosal Immune Responses; Nasal Epithelium; Nasal cavity; Nose; Pathway interactions; Patient Recruitments; Patients; Pharmaceutical Preparations; Physiological; Physiology; Relapse; Research; Resolution; Role; Shotguns; Staphylococcus aureus; Staphylococcus epidermidis; Structure of mucous membrane of nose; Subgroup; Swab; Taxonomy; Therapeutic immunosuppression; Time; Upper respiratory tract; Variant; Vasculitis; Virulence; Visit; Wegener' s Granulomatosis; Work; early detection biomarkers; epidemiology study; experience; genome sequencing; genomic data; genomic profiles; high risk; host microbiota; host-microbe interactions; insight; interest; metabolomics; metagenomic sequencing; microbial; microbiome; microbiome research; microbiota; nasal microbiome; nasal microbiota; new therapeutic target; novel; personalized medicine; relapse risk; rhinosinusitis; trait; treatment strategy; whole genome

PROJECT SUMMARY/ABSTRACT Granulomatosis with polyangiitis (GPA) is a systemic vasculitis characterized by granulomatous inflammation and frequent relapses. Rhinosinusitis is a distinguishing feature of GPA and associated with a higher risk of relapse. While our knowledge of the immunopathogenesis of GPA has advanced, little is known about the triggers of disease activity. In particular, two questions remain unanswered: 1) what ignites disease activity in GPA? 2) why, despite similarities in clinical presentation and immunosuppressive therapy, are some patients more likely to relapse than others? Mechanistic and epidemiologic studies suggest microbes, in particular nasal microbiota, may be an important environmental activator of GPA. To deepen our understanding of the potential effects of the nasal microbiome on disease activity in GPA, our group used high-throughput sequencing methods to comprehensively investigate the thousands of resident microbiota in the nasal cavity of patients with GPA. Our preliminary findings using 16S gene sequencing showed dynamic changes in the nasal microbiome prior to the onset of relapse in GPA and, conversely, temporal stability in those with quiescent disease. Sequencing the 16S gene was an appropriate initial approach to characterize the microbiome but is limited in species/strain resolution (identifies genus level at best) and ascertaining functional information. In order to investigate the hypothesis that species- and strain-specific interactions between nasal bacteria activate the mucosal immune response in the nasal cavity of patients with GPA, we first need to: 1) increase taxonomic resolution to identify species/strains of bacteria associated with GPA relapse, 2) demonstrate feasibility of culturing bacteria of interest for use in future mechanistic studies, and 3) evaluate whether microbial genetic pathways (e.g., metabolites or virulence-related genes) are associated with relapse in GPA. The objective of the proposed study is to identify, culture, and functionally characterize the bacterial species and strains that are associated with disease activity in patients with GPA. Beyond taxonomic identification (what microbes are present), understanding the functional composition (what can the microbes do) may discover the mechanisms in which microbes incite or perpetuate autoimmunity. This work will directly lead to deeper investigations into the mechanisms used by nasal bacteria to activate host immunity. Understanding the key genetic and functional traits that affect host physiology and mediate cross-species relationships may lead to the development of novel therapies targeting microbes or their products as well as biomarkers of early disease detection in GPA.

项目摘要/摘要 肉芽肿性肉芽肿（GPA）是一种全身性血管炎，其特征是肉芽肿性炎症 和经常复发。鼻孔炎是GPA的显着特征，与更高的风险有关 复发。尽管我们对GPA的免疫发病的了解已经提高了，但对此知之甚少 疾病活动的触发因素。特别是，两个问题仍未得到解决：1）在 GPA？ 2）为什么有些患者在临床表现和免疫抑制治疗方面相似 比其他人更可能复发？机械和流行病学研究表明微生物，特别是 鼻微生物群可能是GPA的重要环境激活剂。加深我们对 鼻微生物组对GPA疾病活性的潜在影响，我们的小组使用了高通量 测序方法是为了全面研究鼻腔中成千上万的居民微生物群 GPA患者。我们使用16S基因测序的初步发现显示了鼻腔的动态变化 在GPA复发发作之前的微生物组，相反 疾病。测序16S基因是表征微生物组的适当初始方法，但IS 限制物种/应变分辨率（充其量可以识别属水平）并确定功能信息。在 为了研究鼻细菌之间物种和菌株特异性相互作用的假设 激活GPA患者鼻腔腔中的粘膜免疫反应，我们首先需要：1）增加 分类分辨率鉴定与GPA复发相关的细菌物种/菌株，2）证明 在未来的机械研究中使用感兴趣的细菌培养细菌的可行性，3）评估是否是否 微生物遗传途径（例如代谢产物或与毒力相关的基因）与GPA复发有关。 拟议的研究的目的是识别，培养并在功能上表征细菌物种 以及与GPA患者疾病活性相关的菌株。超越分类学识别 （存在什么微生物），了解功能组成（微生物可以做什么）可能 发现微生物促进自身免疫性的机制。这项工作将直接导致 对鼻细菌用来激活宿主免疫的机制进行了更深入的研究。理解 影响宿主生理和介导跨物种关系的关键遗传和功能性状可能 导致靶向微生物或其产品的新型疗法以及早期的生物标志物的发展 GPA中的疾病检测。