Description and Characterisation of a Novel Model of Persistent Infection with Streptococcus Pneumoniae in the Lower Airways of Mice

This thesis reports the development of a murine model of low-level, long-term colonisation of the lower respiratory tract with S. pneumoniae, which would mimic the bacterial colonisation observed in COPD and severe asthma in humans. For a successful model of persistent infection, viable pneumococci would be recovered from the lower respiratory tract for a minimum of 28 days, mice would be asymptomatic but there would be an inflammatory response. After a single intranasal challenge of S. pneumoniae strain LgSt215, CBA/Ca mice had recoverable numbers of viable pneumococci in the lower airways for at least 28 days post-infection, with an accompanying inflammatory response that consisted of a transient neutrophilia but progressed to being predominantly monocytic with foci of fibroplasia at the transitional airways from 14 days post-infection. The next stage was to combine the new model of persistent pneumococcal infection with models that mimic other pathologies observed in COPD and asthma. Consequently an acute model of lipopolysaccharide-induced lung injury was combined with the model of persistent infection. This resulted in an increase in the number of neutrophils in the lower airways. However when the persistent pneumococcal infection model was combined with a model of ovalbumin-induced eosinophilic inflammation, the number of eosinophils induced was reduced, suggesting that the inflammatory response was no longer one of allergy, but mediated primarily by a Th1-mediated immune response. The observed phenotype mimicked the non-eosinophilic phenotype observed in half of mild-to-moderate asthmatics. A new NADPH oxidase 4 inhibitor was tested in this combined model of inflammation, and it was seen that after administration of this inhibitor an improvement in ciliary function was observed. This model of persistent infection is an ideal tool to test hypotheses of triggers of exacerbation and for study of the role that bacterial infection play in the progression of COPD and asthma.