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Aus Dem Institut Für Molekulare Pathogenese Des Friedrich - Loeffler - Instituts, Bundesforschungsinstitut Für Tiergesundheit, Standort Jena

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Aus Dem Institut Für Molekulare Pathogenese Des Friedrich - Loeffler - Instituts, Bundesforschungsinstitut Für Tiergesundheit, Standort Jena Aus dem Institut für molekulare Pathogenese des Friedrich - Loeffler - Instituts, Bundesforschungsinstitut für Tiergesundheit, Standort Jena eingereicht über das Institut für Veterinär - Physiologie des Fachbereichs Veterinärmedizin der Freien Universität Berlin Evaluation and pathophysiological characterisation of a bovine model of respiratory Chlamydia psittaci infection Inaugural - Dissertation zur Erlangung des Grades eines Doctor of Philosophy (PhD) an der Freien Universität Berlin vorgelegt von Carola Heike Ostermann Tierärztin aus Berlin Berlin 2013 Journal-Nr.: 3683 Gedruckt mit Genehmigung des Fachbereichs Veterinärmedizin der Freien Universität Berlin Dekan: Univ.-Prof. Dr. Jürgen Zentek Erster Gutachter: Prof. Dr. Petra Reinhold, PhD Zweiter Gutachter: Univ.-Prof. Dr. Kerstin E. Müller Dritter Gutachter: Univ.-Prof. Dr. Lothar H. Wieler Deskriptoren (nach CAB-Thesaurus): Chlamydophila psittaci, animal models, physiopathology, calves, cattle diseases, zoonoses, respiratory diseases, lung function, lung ventilation, blood gases, impedance, acid base disorders, transmission, excretion Tag der Promotion: 30.06.2014 Bibliografische Information der Deutschen Nationalbibliothek Die Deutsche Nationalbibliothek verzeichnet diese Publikation in der Deutschen Nationalbibliografie; detaillierte bibliografische Daten sind im Internet über <http://dnb.ddb.de> abrufbar. ISBN: 978-3-86387-587-9 Zugl.: Berlin, Freie Univ., Diss., 2013 Dissertation, Freie Universität Berlin D 188 Dieses Werk ist urheberrechtlich geschützt. Alle Rechte, auch die der Übersetzung, des Nachdruckes und der Vervielfältigung des Buches, oder Teilen daraus, vorbehalten. Kein Teil des Werkes darf ohne schriftliche Genehmigung des Verlages in irgendeiner Form reproduziert oder unter Verwendung elektronischer Systeme verarbeitet, vervielfältigt oder verbreitet werden. Die Wiedergabe von Gebrauchsnamen, Warenbezeichnungen, usw. in diesem Werk berechtigt auch ohne besondere Kennzeichnung nicht zu der Annahme, dass solche Namen im Sinne der Warenzeichen- und Markenschutz-Gesetzgebung als frei zu betrachten wären und daher von jedermann benutzt werden dürfen. This document is protected by copyright law. No part of this document may be reproduced in any form by any means without prior written authorization of the publisher. Alle Rechte vorbehalten | all rights reserved © Mensch und Buch Verlag 2015 Choriner Str. 85 - 10119 Berlin [email protected] – www.menschundbuch.de „Die Welt ist groß und Erkenntnis lauert überall.“ G. Brem* Meinen Eltern und Stephan in Liebe und Dankbarkeit gewidmet _______________________________________________ *Prof. Dr. med. vet. Gottfried Brem (Wien): „Warum die Tiermedizin Grundlagenforschung braucht.“ Festvortrag im Rahmen des 19. Symposiums der Fachgruppe Physiologie und Biochemie der Deutschen Veterinärmedizinischen Gesellschaft; Hannover,14.-16,o2.2010. I Table of contents 1 Introduction ................................................................................................................ 1 1.1 General background .................................................................................................. 1 1.2 Chlamydiae ................................................................................................................. 2 1.2.1 Taxonomic classification ............................................................................................. 2 1.2.2 Chlamydial developmental cycle and persistence........................................................ 4 1.2.3 Chlamydia psittaci ....................................................................................................... 5 1.3 Bovines as a suitable model species .......................................................................... 9 1.3.1 Structural and functional peculiarities of the bovine respiratory tract ......................... 9 1.3.2 Age dependent peculiarities ....................................................................................... 12 1.3.3 Assessment of pulmonary functions in calves ........................................................... 12 1.4 Aims of the project ................................................................................................... 14 1.5 Design of the project ................................................................................................ 14 2 Publications and disclosure of personal contributions ......................................... 17 2.1 STUDY 1: A Bovine Model of Respiratory Chlamydia psittaci Infection: Challenge Dose Titration ......................................................................................... 18 2.2 STUDY 2: Dose-dependent effects of Chlamydia psittaci infection on pulmonary gas exchange, innate immunity and acute-phase reaction in a bovine respiratory model ......................................................................................... 33 2.3 STUDY 3: Infection, Disease, and Transmission Dynamics in Calves after Experimental and Natural Challenge with a Bovine Chlamydia psittaci Isolate ........................................................................................................................ 44 2.4 STUDY 4: Evaluation of pulmonary dysfunctions and acid-base imbalances induced by Chlamydia psittaci in a bovine model of respiratory infection ......... 57 Correction: Evaluation of pulmonary dysfunctions and acid-base imbalances induced by Chlamydia psittaci in a bovine model of respiratory infection................................................................................................. 80 3 Discussion .................................................................................................................. 81 3.1 Factors determining, influencing and characterising the model ......................... 81 3.1.1 Methodological aspects .............................................................................................. 81 3.1.2 Biological factors ....................................................................................................... 86 3.2 Complex pathogenetic and pathophysiological implications and their consequences for the bovine host ............................................................................ 96 3.2.1 Innate and adaptive immune response ....................................................................... 96 3.2.2 Pathogenetic interactions in the bovine lung ........................................................... 100 3.3 Excretion and transmission of C. psittaci in bovines ........................................... 105 II 3.4 Conclusions and directions for further research ................................................ 106 4 Summary ................................................................................................................. 108 5 Zusammenfassung .................................................................................................. 111 6 Bibliography ........................................................................................................... 115 7 List of abbreviations .............................................................................................. 136 8 List of figures .......................................................................................................... 140 9 List of tables ............................................................................................................ 142 10 List of publications ................................................................................................. 144 10.1 Publications in peer-reviewed journals ................................................................ 144 10.2 Published Abstracts ............................................................................................... 145 11 Danksagung ............................................................................................................ 153 12 Selbstständigkeitserklärung .................................................................................. 154 1 1 Introduction 1.1 General background Zoonoses, regardless whether emerging or classical, are not only a challenge for human public health, but also cause significant economic losses in animal husbandry (Christou 2011). Thus, interdisciplinary research networks dealing with zoonotic infectious pathogens were established by the German Federal Ministry of Education and Research (BMBF). Chlamydiales, an order of gram-negative, obligate intracellular bacteria, include several species associated with well-documented and suspected zoonotic risks (Wheelhouse and Longbottom 2012). Until recently, research was hampered by the lack of genetic systems and cell-free culturing applicable to chlamydiae (Wang et al. 2011; Omsland et al. 2012). So the overall aims of the network “Zoonotic Chlamydiae” included (i) the elucidation of molecular pathogenesis, (ii) the improvement of diagnostic tools, and (iii) the evaluation of medical treatment for human chlamydial infections. An animal model mimicking closely the relevant characteristics of human disease is still a key element for understanding the underlying mechanisms of disease pathogenesis. Moreover, a valid animal model is a prerequisite for development and efficacy testing of therapeutics and vaccines (Kahn et al. 2009). The present work is an integral part of the above mentioned zoonotic network (‘Subproject Two’) and focused on the introduction and characterisation of a biologically relevant animal model. The main objective was
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