TY  - UNPB
N1  - Unpublished
TI  - Colonisation-induced protection against Streptococcus pneumoniae disease
AV  - public
Y1  - 2011/01/28/
EP  - 332
M1  - Doctoral
A1  - Cohen, J.M.
N2  - 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.
ID  - discovery1124359
PB  - UCL (University College London)
UR  - https://discovery.ucl.ac.uk/id/eprint/1124359/
ER  -