Document Type Doctoral Thesis Author Cockeran, Riana URN etd-09192005-110614 Document Title Effects of sub-lethal concentrations of pneumolysin on the proinflammatory activities of human neutrophils in vitro Degree DPhil Department Immunology Supervisor
Advisor Name Title Prof R Anderson Committee Chair Keywords
- streptococcus pneumoniae toxins
- airway medicine infection
Date 2003-04-01 Availability unrestricted AbstractThe Streptococcus pneumoniae-derived toxin, pneumolysin, has been reported to augment neutrophil-mediated inflammatory responses in murine models of experimental infection of the airways, and to favour invasive pneumococcal disease. The laboratory research presented in this thesis has been designed to investigate the possible proinflammatory interactions of pneumolysin with human neutrophils in vitro, as well as the underlying mechanisms of these.
Addition of pneumolysin (0.0167 - 41.75 ng/ml) to neutrophils caused dose-related enhancement of the following proinflammatory activities of these cells: superoxide generation, elastase release, expression of the β2-integrin CR3, phospholipase A2 activity and production of leukotriene B4 and prostaglandin E2, oxidative inactivation of α-1-proteinase inhibitor, and synthesis and release of interleukin-8. Pneumolysin-mediated enhancement of these neutrophil activities was observed in the absence of detectable cytotoxicity and was most striking when the toxin was added together with the bacterial chemoattractant N-formyI-L-methionyl-L-leucyl-L-pnenylalanine (FMLP, 1 µM).
Treatment of neutrophils with pneumolysin also resulted in uncontrolled influx of Ca2+ into the cells in the setting of membrane depolarisation and efflux of K+, which appeared to be a consequence of the pore forming actions of the toxin. Importantly, the proinflammatory interactions of pneumolysin with neutrophils were completely attenuated by exclusion of Ca2+ from the cell-suspending medium.
These observations identify novel proinflammatory properties of pneumolysin which result from pore formation in the plasma membrane, influx of Ca2+ and augmentation of Ca2+ -activitable neutrophil functions.
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Please cite as follows:
Cockeran, R 2003, Effects of sub-lethal concentrations of pneumolysin on the proinflammatory activities of human neutrophils in vitro, DPhil thesis, University of Pretoria, Pretoria, viewed yymmdd < http://upetd.up.ac.za/thesis/available/etd-09192005-110614/ >
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