Background: Severe bacterial infections and sepsis are a major global cause of mortality and morbidity and with the number of antibiotic resistance cases on the rise. Despite the introduction of treatment guidelines such as those implemented by the surviving sepsis campaign mortality remains high and new therapies are desperately needed. One new therapy, which may be of benefit, is P4 therapy the combination of the immunomodulating peptide P4 and intravenous immunoglobulin (IVIG). The ability of P4 to augment phagocytosis in models of pneumococcal infections, decreasing bacterial burden and improving survival has previously been shown. This thesis goes on to investigate the efficacy of P4 therapy in models of Gram-negative infections, with and without antibiotics and in ex vivo studies from patients with severe community acquired pneumonia (CAP). Methods: Murine models of Escherichia coli and Klebsiella pneumoniae infection were used to evaluate the efficacy of P4 peptide with IVIG in the treatment of severe Gram-negative infections. Flow cytometry and ELISA were used to assessed immune responses to infection with P4 treatment. Neutrophils from patients with severe CAP were isolated and their responses to P4 assessed with ex vivo phagocytosis assays and flow cytometry. In vivo and ex vivo studies were performed with naïve mice and tissue culture cell lines to evaluate the effect of P4 on neutrophil receptor expression and the binding of P4 peptide to cells. Results: Treatment with P4 and IVIG in combination with antibiotics led to significant improvements in survival and bacterial burden in Klebsiella pneumoniae infection. Treatment of Escherichia.coli infection with P4 and IVIG in combination with antibiotics showed no benefits over treatment with antibiotic with IVIG, this was likely due to the infection being too severe. In neutrophils from CAP patients increases in bacterial killing when treated with P4 in phagocytosis assays were seen in 60% of patient. Patients who did not respond to the P4 treatment showed higher levels of IL-8 and IL-10 in their serum and higher disease severity scores. Conclusions: P4 treatment showed efficacy in the treatment of Klebsiella infection but data from E. coli infections and ex vivo treatment of CAP patient neutrophils suggest that infection severity and levels of IL-8 and IL-10 may effect treatment success. P4 could be a potential new treatment option for patients with severe bacterial infections but further studies are needed to better establish which patients would benefit from this treatment and the influence of host immune status on treatment efficacy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:722038 |
| Date | January 2017 |
| Creators | Gore, S. |
| Publisher | University of Liverpool |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://livrepository.liverpool.ac.uk/3006121/ |
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