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

项目总结/文摘

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.