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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:587603 |
| Date | January 2011 |
| Creators | Cohen, J. M. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1124359/ |
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