Background: Bacterial infections, particularly those of the respiratory tract, are a serious cause of mortality worldwide despite vaccinations and optimized treatment strategies. Prior to the introduction of antibiotics, passive immunotherapy was widely used to treat a range of bacterial infections. A successful opsonin based treatment, however, requires effective clearance by phagocytic cells. Augmented passive immunotherapy (API) is a novel treatment strategy that combines pathogen specific immunoglobulin (IVIG) and the immunomodulating peptide P4 to treat fulminant bacterial infections. Using in vivo, in vitro and ex vivo models of pneumococcal infection, this thesis aimed to describe host responses to API. Methods: The in vivo recruitment and activation of phagocytes following peptide treatment in the absence of infection was characterised using flow cytometry and electron microscope imaging. These findings were translated to murine infection models by treating pneumococcal septicemia with intravenous peptide administration and pneumococcal pneumonia with intranasal peptide administration. In vitro phagocytosis killing assays were used to determine the ability of P4 to augment bacterial killing of a range of pneumococcal serotypes and describe the involvement of phagocytic Fcγ receptors. Ex vivo assays of phagocytic function of human neutrophil and alveolar macrophages were used to translate murine and in vitro findings. Results: Peptide administration in the absence and presence of infection led to rapid recruitment of monocytes, neutrophils and macrophages and their activation as demonstrated by increased FcγR expression. Intravenous peptide administration during septicemia led to significantly increased survival rates in models of invasive and acute invasive pneumococcal diseases in young and aged mice of various genetic backgrounds. Intranasal peptide administration during pneumonia prevented the onset of septicemia and subsequent host mortality. Increased survival was associated with reduced bacterial burden in affected tissue. Peptide treatment of neutrophil cell lines, human neutrophils and alveolar macrophages modulates FcγR expression resulting in augmented phagocytic killing of opsonised pneumococci. Conclusion: Augmented passive immunotherapy is a synergistic treatment that enhances natural host immune responses to infection by opsonizing pathogens and inducing their effective phagocytic clearance.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:579338 |
| Date | January 2012 |
| Creators | Bangert, Mathieu |
| Contributors | Gordon, Stephen; Kadioglu, Aras |
| Publisher | University of Liverpool |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://livrepository.liverpool.ac.uk/10993/ |
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