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Effects of a Primary Influenza Infection on Susceptibility to a Secondary Streptpcoccus Pneumoniae Infection

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Effects of a Primary Influenza Infection on Susceptibility to a Secondary Streptpcoccus Pneumoniae Infection EFFECTS OF A PRIMARY INFLUENZA INFECTION ON SUSCEPTIBILITY TO A SECONDARY STREPTOCOCCUS PNEUMONIAE INFECTION by Lynnelle Ann McNamee A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Veterinary Molecular Biology MONTANA STATE UNIVERSITY Bozeman, Montana August 2006 © COPYRIGHT by Lynnelle Ann McNamee 2006 All Rights Reserved ii APPROVAL of a dissertation submitted by Lynnelle Ann McNamee This dissertation has been read by each member of the dissertation committee and has been found to be satisfactory regarding content, English usage, format, citations, bibliographic style, and consistency, and is ready for submission to the Division of Graduate Education. Dr. Allen G. Harmsen Approved for the Department of Veterinary Molecular Biology Dr. Mark T. Quinn Approved for the Division of Graduate Education Dr. Carl A. Fox iii STATEMENT OF PERMISSION TO USE In presenting this dissertation in partial fulfillment of the requirements for a doctoral degree at Montana State University, I agree that the library shall make it available to borrowers under rules of the Library. I further agree that copying of this dissertation is allowable only for scholarly purposes, consistent with “fair use” as prescribed in the U.S. Copyright Law. Requests for extensive copying or reproduction of this dissertation should be referred to ProQuest Information and Learning, 300 North Zeeb Road, Ann Arbor, Michigan 48106, to whom I have granted “the exclusive right to reproduce and distribute my dissertation in and from microform along with the non- exclusive right to reproduce and distribute my abstract in any format in whole or in part.” Lynnelle Ann McNamee August, 2006 iv ACKNOWLEDGEMENTS My graduate work would not have been possible without the help of several people. I would like to thank my graduate advisor Dr. Allen Harmsen for all of his support and guidance throughout my graduate education at Montana State University. He has been an excellent mentor and has taught me the importance of fully understanding my results. I hope to one day be as excellent of a scientist as him. I would also like to thank the past and present members of my graduate committee (Drs. David Pascual, Michele Hardy, Ross Taylor, Charles Kankelborg, Al Jesaitis, and Luanne Hall-Stoodley). They helped to shape the goals and direction for the research for my dissertation. My research could not have been completed without the help of the excellent scientists in the Harmsen lab. They have offered me technical assistance and have engaged me in stimulating discussions about my research project. In particular, I would like to thank Dr. Melanie Rutkowski, who has been an exceptional colleague and friend. In addition, I would like to thank everyone in the Veterinary Molecular Biology Department and the Animal Resource Center for all of their help and support throughout my graduate education. I would not be where I am today if it were not for the support, love, and encouragement of my family. They have always supported me in my educational endeavors and told me I could be whatever I wanted to be when I grew up, for which I am very thankful. Finally, I would like to thank Owen Pittet, who not only let me write my thesis in his apartment, but also helped me through the process with his continual support, love, and encouragement. v TABLE OF CONTENTS 1. INTRODUCTION ..........................................................................................................1 Influenza Background.....................................................................................................1 Influenza Virus............................................................................................................1 Hemagglutinin.............................................................................................................4 Neuraminidase ............................................................................................................5 Antigenic Drift............................................................................................................5 Antigenic Shift............................................................................................................6 Influenza Virus Infection ............................................................................................6 Influenza Pandemics ...................................................................................................9 Current Pandemic Threat: H5N1 ...............................................................................9 Influenza Virus Vaccine ...........................................................................................11 Antivirals...................................................................................................................12 Secondary Bacterial Infections .................................................................................13 Streptococcus pneumoniae Background.......................................................................13 Classification.............................................................................................................13 Innate and Adaptive Immune Responses to S. pneumoniae .....................................14 S. pneumoniae Infections..........................................................................................15 Antibiotics: Treatment of S. pneumoniae and Resistance .......................................17 S. pneumoniae Vaccines ...........................................................................................18 Adhesins....................................................................................................................19 Pneumococcal Virulence Factors/Surface Proteins ..................................................20 Capsule................................................................................................................20 Cell Wall .............................................................................................................20 Choline Binding Proteins....................................................................................21 Other Virulence Factors......................................................................................22 Effects of Influenza Infection on Susceptibility to S. pneumoniae infection ...............24 Tissue Damage..........................................................................................................25 Neutrophil Function..................................................................................................27 Other Possible Mechanisms of Increased Susceptibility ..........................................29 Hypothesis.....................................................................................................................30 2. BOTH INFLUENZA-INDUCED NEUTROPHIL DYSFUNCTION AND NEUTROPHIL-INDEPENDENT MECHANISMS CONTRIBUTE TO INCREASED SUSCEPTIBILITY TO A SECONDARY STREPTOCOCCUS PNEUMONIAE INFECTION .................................................................................................................32 Introduction...................................................................................................................32 Materials and Methods..................................................................................................35 Infectious Agents ......................................................................................................35 Mice ..........................................................................................................................36 vi TABLE OF CONTENTS-CONTINUED Infection Model.........................................................................................................36 Tissue Preparation.....................................................................................................37 Neutrophil ROS Generation and S. pneumoniae Association/Phagocytosis Detection.........................................................................37 Lung Cytokine Levels...............................................................................................40 Statistical Analysis....................................................................................................40 Results...........................................................................................................................41 Peak Susceptibility to Secondary S. pneumoniae infection is at 6 Days after Influenza Infection........................................................................41 Effects of RB6-8C5 Depletion on Blood and BALF neutrophil numbers ........................................................................................42 Neutrophil-Dependent Mechanisms of Increased Susceptibility to S. pneumoniae Infection ................................................................46 Influenza-Induced Changes in Neutrophil-Independent Mechanisms Increase Susceptibility to S. pneumoniae infection .............................48 Neutrophil Function Assays......................................................................................49 Influenza Infection Reduces S. pneumoniae Association with Neutrophils....................................................................................51 Influenza Infection Reduces ROS Production by Neutrophils .................................55 Effects of Influenza Infection and/or S. pneumoniae Infection(s) on Lung Cytokine Production...................................................................................59
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