Title page for ETD etd-09192005-110614


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
  • neutrophils
  • inflammation
Date 2003-04-01
Availability unrestricted
Abstract
The 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 M).

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.

2003 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria.

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/ >

H1045/ag

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