Characterizing the subepithelial mucosa in chronic rhinosinusitis: influences of microbes and innate immunity.

Abstract

Chronic rhinosinusitis (CRS) is a clinical condition associated with persistent inflammation of the mucosa of the nose and paranasal sinuses. A significant body of evidence suggests that the mucosal inflammatory response may be caused by an immunologically mediated reaction to the presence of bacteria and fungi colonizing the region. Inflammation of mucosa around the sinus ostia leads to obstruction of drainage pathways, and is thought to create a local environment that facilitates further growth of microorganisms. However, to date, culture directed antimicrobial therapy had shown relatively limited efficacy. Recent observation of subepithelial bacterial colonies, predominantly Staphylococcus aureus, identified a new type of microbiological niche that is not detectable by conventional mucus swab culture techniques, and also relatively resistant to conventional antibiotics. Also, S. aurues were found to exist within the mucosa without triggering a host immune response, which suggests the possibility of host immunomodulation. This thesis aimed to further characterize the nature of subepithelial S. aureus by comparing its genotype and phenotype to the S. aureus cultured from the mucosal surface – however no discernable differences were identified. The mucosal innate immunity was investigated in view of the apparent immunotolerance of intramucosal bacteria, and a significant skew towards alternatively activated, immunotolerant macrophages was observed in CRS mucosa. Non-culture, non-histology dependent molecular techniques of microbiological analysis were utilized to compare the surface and intramucosal microbiological environments, and confirmed the hypothesis that the subepithelial microbiological niche is distinct from the mucosal surface niche. Novel therapeutic options targeting subepithelial bacterial colonies and chronic mucosal inflammation were also investigated, with results suggesting the possibility of therapeutic efficacy. This thesis advances the hypothesis that microbes and the innate immunity have inseparable interactions in the pathogenesis of CRS.