%0 Thesis
%9 Doctoral
%A Cohen, J.M.
%B ICH - Infectious Diseases and Microbiology
%D 2011
%F discovery:1124359
%I UCL (University College London)
%P 332
%T Colonisation-induced protection against Streptococcus pneumoniae disease
%U https://discovery.ucl.ac.uk/id/eprint/1124359/
%X Streptococus pneumoniae is an important human pathogen, yet in most individuals it  establishes only transient nasopharyngeal colonisation without causing disease. Using  murine models, this thesis explores the hypothesis that colonisation induces acquired  immune responses which protect against subsequent pneumonia.  Colonisation models with wild-type (WT) and mutant S. pneumoniae were established  in outbred CD1 mice. Mutants lacked either capsule or lipoproteins, or were  auxotrophs unable to replicate in vivo. WT colonisation protected against subsequent  pneumonia. Mutants were cleared more rapidly than WT, were not immunogenic and  did not protect. When the auxotroph was supplemented, colonisation,  immunogenicity and protection were improved, suggesting duration of a colonisation  event is an important factor in determining immunogenicity. This may be one factor  explaining the poor immunogenicity of the other mutants.  The mechanism by which previous colonisation protected against subsequent lethal  pneumonia was then defined in a series of studies in inbred CBA/Ca mice.  Colonisation induced both mucosal and systemic antibody responses to bacterial  surface antigens but not capsule. There was also evidence of more robust cytokine  production during subsequent pneumonia, including systemic and mucosal IL-17  responses dependant on the presence of CD4-cells. Protection was primarily against  systemic invasion following pneumonia. Passive transfer studies and experiments  using genetically modified mice demonstrated that systemic antibody was both  necessary and sufficient to protect, and in vitro and in vivo models showed this to be  via opsonophagocytosis and bloodstream clearance of bacteria. Antigenic protein  targets of protective serum were defined using Western blotting and multiplex bead  immunoassay techniques. Overall this thesis demonstrates that nasopharyngeal colonisation can protect against  lethal pneumonia in mice via opsonophagocytic antibody against surface proteins thus  preventing bacteraemia.