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

项目摘要/摘要 肉芽肿病合并多血管炎(GPA)是一种以肉芽肿性炎症为特征的系统性脉管炎。 以及频繁的复发。鼻-鼻窦炎是GPA的一个显著特征，并与患 旧病复发。虽然我们对GPA的免疫发病机制的了解有所进步，但对GPA的免疫致病机制知之甚少 疾病活动的诱因。具体地说，有两个问题仍然没有得到回答：1)什么在 GPA？2)为什么，尽管临床表现和免疫抑制治疗相似，但有些患者 比其他人更容易复发？机械学和流行病学研究表明，微生物尤其是 鼻腔微生物区系可能是GPA的重要环境激活剂。为了加深我们对 鼻部微生物群对GPA疾病活动性的潜在影响，我们小组使用了高通量 应用测序方法全面调查辽宁地区居民鼻腔内数千个微生物区系 有GPA的患者。我们使用16S基因测序的初步发现显示鼻腔的动态变化 GPA中复发开始前的微生物组，反之，静止期患者的时间稳定性 疾病。对16S基因进行测序是描述微生物组特征的合适的初始方法，但 在物种/菌株分辨率(最多识别属水平)和确定功能信息方面受到限制。在……里面 为了调查鼻腔细菌之间的物种和菌株特异性相互作用的假说 激活GPA患者鼻腔粘膜免疫反应，首先需要：1)增加 识别与GPA复发相关的细菌物种/菌株的分类学解决方案，2)证明 培养感兴趣的细菌用于未来机制研究的可行性，以及3)评估 微生物遗传途径(例如，代谢物或毒力相关基因)与GPA的复发有关。 本研究的目的是对细菌进行鉴定、培养和功能鉴定。 以及与GPA患者疾病活动相关的菌株。超越分类鉴定 (存在什么微生物)，了解功能组成(微生物能做什么)可能 发现微生物激发或维持自身免疫的机制。这项工作将直接导致 更深入地研究鼻腔细菌激活宿主免疫的机制。理解 影响寄主生理和调节跨物种关系的关键遗传和功能性状可能 导致针对微生物或其产品以及早期生物标记物的新疗法的开发 GPA中的疾病检测。

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.