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Listeriolysin O and Pneumolysin: Effects on Intracellular Calcium Homeostasis and Epithelial Barrier Integrity

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Listeriolysin O and Pneumolysin: Effects on Intracellular Calcium Homeostasis and Epithelial Barrier Integrity Listeriolysin O and Pneumolysin: Effects on intracellular calcium homeostasis and epithelial barrier integrity Martin Leustik AND EPITHELIAL BARRIER FUNCTION 2+ LLO & PLY – Ca INAUGURAL DISSERTATION submitted to the Faculty of Medicine édition scientifique in partial fulfilment of the requirements VVB LAUFERSWEILER VERLAG for the PhD-degree VVB LAUFERSWEILER VERLAG of the Faculties of Veterinary Medicine and Medicine STAUFENBERGRING 15 ISBN: 978-3-8359-5996-5 of the Justus Liebig University Giessen, Germany D-35396 GIESSEN MARTIN LEUSTIK Tel: 0641-5599888 Fax: -5599890 [email protected] www.doktorverlag.de 9 783835 959965 édition scientifique VVB LAUFERSWEILER VERLAG VVB Das Werk ist in allen seinen Teilen urheberrechtlich geschützt. Jede Verwertung ist ohne schriftliche Zustimmung des Autors oder des Verlages unzulässig. Das gilt insbesondere für Vervielfältigungen, Übersetzungen, Mikroverfilmungen und die Einspeicherung in und Verarbeitung durch elektronische Systeme. 1. Auflage 2013 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the Author or the Publishers. 1st Edition 2013 © 2013 by VVB LAUFERSWEILER VERLAG, Giessen Printed in Germany VVB LAUFERSWEILERédition scientifique VERLAG STAUFENBERGRING 15, D-35396 GIESSEN Tel: 0641-5599888 Fax: 0641-5599890 email: [email protected] www.doktorverlag.de Listeriolysin O and Pneumolysin: Effects on intracellular calcium homeostasis and epithelial barrier integrity Inaugural Dissertation submitted to the Faculty of Medicine in partial fulfillment of the requirements for the PhD-Degree of the Faculties of Veterinary Medicine and Medicine of the Justus-Liebig-University Giessen by Martin Leustik of Klagenfurt, Austria Giessen 2012 From the Institute of Medical Microbiology Director: Prof. Dr. Trinad Chakraborty Faculty of Medicine of the Justus-Liebig-University Giessen First Supervisor and Committee Member: Prof. Dr. T. Chakraborty Second Supervisor and Committee Member: Prof. Dr. W. Kühlbrandt Committee Members: Prof. Dr. M. Diener Prof. Dr. J. Lohmeyer Date of Doctoral Defence: 4 th February 2013 Declaration “I declare that I have completed this dissertation single-handedly without the unauthorized help of a second party and only with the assistance acknowledged therein. I have appropriately acknowledged and referenced all text passages that are derived literally from or are based on the content of published or unpublished work of others, and all information that relates to verbal communications. I have abided by the principles of good scientific conduct laid down in the charter of the Justus Liebig University of Giessen in carrying out the investigations described in the dissertation.” Martin Leustik TABLE OF CONTENTS Table of Contents Listeriolysin O and Pneumolysin:______________________________________ I Inaugural-Dissertation _______________________________________________ I Martin Leustik ______________________________________________________ I Giessen 2012_______________________________________________________ I From the Institute of Medical Microbiology _____________________________ II Table of Contents ___________________________________________________ I List of abbreviations________________________________________________ IV 1 Introduction _____________________________________________________ 1 1.1 Bacterial toxins ________________________________________________ 1 1.1.1 AB Toxins ______________________________________________________________ 2 1.1.2 Superantigens __________________________________________________________ 5 1.1.3 Membrane Damaging Toxins _______________________________________________ 6 1.2. Cholesterol dependent Cytolysins _________________________________ 8 1.2.1 Listeriolysin O__________________________________________________________ 12 1.2.2 Pneumolysin___________________________________________________________ 14 1.2.3 Comparison of listeriolysin O and pneumolysin ________________________________ 16 1.3 Objective ___________________________________________________ 17 2 Materials and Methods ___________________________________________ 18 2.1 Equipment and consumables ____________________________________ 18 2.2 Chemicals, inhibitors and media__________________________________ 19 2.3 Handling of bacteria ___________________________________________ 20 2.3.1 Media and solutions for bacteria ___________________________________________ 21 2.3.2 Growing of bacterial cultures ______________________________________________ 21 2.3.3 Preparation of bacterial cultures for infection experiments _______________________ 21 2.3.4 Establishing bacterial growth curves ________________________________________ 22 2.4 Handling of eukaryotic cells _____________________________________ 22 2.4.1 Media and solutions for eukaryotic cells _____________________________________ 22 2.4.2 Cultivation of eukaryotic cells______________________________________________ 23 2.4.3 Preparing eukaryotic cells for calcium measurements and immunofluorescence. _____ 24 2.4.4 Preparing eukaryotic cells for infection assays ________________________________ 24 2.5 Measuring the intracellular calcium concentration and total area covered by cells __________________________________________________________ 25 2.5.1 Video imaging system for fluorescence microscopy ____________________________ 25 2.5.2 Measuring intracellular calcium concentrations ________________________________ 26 2.5.3 Measuring the total area covered by cells ____________________________________ 26 I TABLE OF CONTENTS 2.6 Infection assay _______________________________________________ 26 2.7 Bacterial survival assay ________________________________________ 27 2.8 Immunofluorescence __________________________________________ 27 2.9 Purification of Listeriolysin O and Pneumolysin ______________________ 28 2.9.1 Listeriolysin O__________________________________________________________ 28 2.9.2 Pneumolysin___________________________________________________________ 29 2.10 Crystal structure of LLO and target selection for mutations ____________ 30 2.10.1 Generation, expression and purification of LLO mutants________________________ 30 2.11 Statistical Analysis ___________________________________________ 31 3 Results ________________________________________________________ 32 3.1 Sublytic concentrations of Listeriolysin O disturb cellular calcium homeostasis, weaken epithelial monolayers and enable the effective invasion of L. monocytogenes _________________________________________________ 32 2+ 3.1.1 Purified LLO triggers an increase in [Ca ]i in Caco-2 cells _______________________ 32 3.1.2 The activity of LLO is markedly increased after exposure to reducing conditions______ 35 3.1.3 Treatment with LLO leads to a reduction of the overall surface area covered by epithelial cells that depends on the influx of calcium ions into the cytoplasm _____________________ 36 3.1.4 Lanthanum reduces L. monocytogenes’ invasiveness in epithelial monolayers and has bactericidal effects at millimolar concentrations ____________________________________ 40 3.2 Assessment of LLO mutants for their ability to form Ca 2+ -permeable pores_ 45 3.3 Pneumolysin has similar effects as Listeriolysin O on calcium homeostasis and epithelial monolayer integrity, releases ER-stored Ca 2+ and mimics hypertonic stress _________________________________________________________ 48 2+ 3.3.1 Purified PLY triggers an increase in [Ca ]i in H441 cells and is more active under reducing conditions _________________________________________________________________ 49 3.3.2 Epithelial monolayers treated with PLY suffer from a reduction of the overall surface area that is caused by the toxin-induced influx of calcium ions into the cytoplasm _____________ 50 3.3.3 Pneumolysin induces a release of ER-stored calcium into the cytoplasm that is not dependent on cellular ion channels______________________________________________ 55 3.3.4 Pneumolysin triggers changes in epithelial cells that are similar to the cellular reaction to hyperosmotic conditions.______________________________________________________ 57 3.3.5 The pneumolysin-triggered loss in cell surface area is dependent on conventional PKC- activity and is inhibited by the TIP peptide ________________________________________ 60 4 Discussion _____________________________________________________ 64 4.1 The role of listeriolysin O in Listeria monocytogenes’ ability to cross the epithelial barrier _________________________________________________ 64 4.1.1 Purified LLO forms Ca 2+ -permeable pores in cultured epithelial cells _______________ 65 4.1.2 Preincubation with a reducing agent strongly increases LLO activity _______________ 66 II TABLE OF CONTENTS 2+ 4.1.3 Treatment with LLO leads to an [Ca ]i –dependent reduction of the overall surface area covered by epithelial cells _____________________________________________________ 66 4.1.4 Lanthanum reduces L. monocytogenes invasiveness in epithelial monolayers and has bactericidal effects at millimolar concentrations ____________________________________ 68 4.1.5 The assessment of LLO mutants allows insights into its function __________________ 72 4.2 Effects of pneumolysin on epithelial monolayers _____________________ 76 4.2.1 Purified pneumolysin forms Ca 2+ -permeable pores in cultured epithelial cells ________ 78 4.2.2 Pneumolysin reduces the overall surface
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