Characterising host-microbe interactions in chronic rhinosinusitis

Abstract

Chronic rhinosinusitis is a morbid and expensive disorder involving persistent inflammation of the nose and sinuses. Despite advances in medical and surgical treatment it remains a major health burden that in many cases is extremely challenging to treat. This in part arises from the limited understanding of its pathogenesis. The inflammatory response observed is complex but appears to include significant defects in some protective mechanisms. Interest in a putative role for micro-organisms as causative agents waned with bacterial culture data indicating limited differences from the flora seen in health. This thesis aimed to bypass the limitations of bacterial culture and use culture-independent techniques to assess the resident flora of the sinuses and closely correlate the presence of micro-organisms to indices of the inflammatory response that define the disorder. The presence of persistent respiratory virus infection was sought but not found to be an aetiological factor. Limited fungi were identified. However colonies of bacteria adherent to the mucosal surface were seen in association with a particular immune cell infiltrate. Small colonies of bacteria were also identified within the mucosa and the bone of the paranasal sinuses that appeared to be actively suppressing the host immune response. While the presence of such colonies within the bone appeared to be sporadic and not related to inflammatory disease they were more prevalent within the mucosa of patients with chronic rhinosinusitis with nasal polyps. Staphylococcus aureus was seen to be a common organism within the mucosa and is well recognized in vitro to have the capacity to elude immunity. The staphylococcal superantigen-like proteins are one of these mechanisms but they were not identified, possibly due to limitations in the sensitivity of the test used. By examining bacteria and inflammation in situ it has been possible to characterise the host-microbe interface in far greater depth than using bacterial culture techniques. This has provided evidence of mechanisms by which bacteria are able to both persist, evading immune detection but also stimulate an inflammatory response. In combination with other recent studies this thesis advances a hypothesis that incorporates bacteria in the pathogenesis of this challenging disorder.