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Insights Into the Origins of Allergic Asthma VIRAL-ALLERGEN INTERACTIONS VIRAL-ALLERGEN INTERACTIONS: INSIGHTS INTO THE ORIGINS OF ALLERGIC ASTHMA. By AMAL A. AL-GARAWI, M.A. A Thesis Submitted to the School of Graduate Studies in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy McMaster University © Copyright by Amal A. Al-Garawi, April 2012 TO MY PARENTS, NORA & ALI FOR THEIR UNCONDITIONAL LOVE, SUPPORT AND NEVER-ENDING PATIENCE. WITH ALL MY LOVE! ii DOCTOR OF PHILOSOPHY (2012) McMaster University (Medical Sciences) Hamilton, Ontario TIT TITLE: Viral-Allergen Interactions: Insights into the Origins of Asthma AUTHOR: Amal A. Al-Garawi, M.A. (Boston University) SUPERVISOR: Dr. Manel Jordana NUMBER OF PAGES: x, 145 iii ABSTRACT Asthma is a chronic immune-inflammatory disease of the airways, characterized by reversible airflow obstruction and airway hyperresponsiveness (AHR), and is associated with the development of airway remodeling. While our understanding of the pathophysiology of allergic asthma has increased remarkably in the last few decades, the origins of the disease remain elusive. Indeed, studies indicate that the prevalence of allergic asthma, has increased dramatically over the last 30 years. Within this context, a number of environmental factors including respiratory viral infections have been associated with the onset of this disease but causal evidence is lacking. The work presented in this thesis examines the interactions between a respiratory viral infection, specifically influenza A, and the common aeroallergen house dust mite (HDM) in an experimental murine model. To this end, we investigated the impact of an acute influenza A infection on the exposure to a subclinical dose of HDM (Chapter 2) and addressed potential underlying immune mechanisms using a global, genomic approach (Chapter 3). Our data demonstrate an enhancement of immune inflammatory responses to HDM and reveals multiple immune pathways by which influenza A may enhance the response to subsequent allergen exposure. Collectively these immune pathways are capable of lowering the threshold of HDM responsiveness. Lastly, as allergic asthma develops in most instances during infancy, we investigated the impact of an influenza A infection on allergen responses in infant mice (Chapter 4). In this setting, acute influenza A infection subverts constitutive allergen hyporesponsiveness thus resulting in iv sensitization, airway inflammation and, ultimately, structural and functional alterations persisting into adulthood. v ACKNOWLEDGEMENTS I would like to extend my sincerest gratitude to my friends and many colleagues, collaborators, students, and faculty who have contributed in many ways to my professional training and growth as a person. To Manel Jordana, my supervisor and Doktorvater, for his incredible insight, guidance, encouragement and patience. To Susanna Goncharova, Tina Walker, Ramzi Fattouh, Derek Chu for their friendship and unparalleled support. To the members of my supervisory committee, Drs. A. J. Coyle, Paul O’Byrne and Martin Stampfli for their insight, support and invaluable contributions. To my colleagues and collaborators, Fernando Botelho, Mainul Husain, Erin Jamula, Brian Jobse, Katherine Arias, Alba Llop, Cheryl-Lynn Moore, Marc Colangelo, Kristen Flader, Josip Marcinko, Joshua Kong Kong, Drs. Jonas Erjefalt, Jennifer Reed, Dora Ilieva, and Alison Humbles as well as the numerous undergraduates that spent time in our lab, for all of their friendship, encouragement and help. To my dear friends, Susanna Hilfer, Erika Cohen and Joseph Kennedy, for sticking with me throughout the years! vi TABLE OF CONTENTS List of Abbreviations…………………………………………………………..viii Preface…………………………………………………………………………ix-x CHAPTER 1: Introduction………………………………………………………1-23 Preface: Asthma and its Impact on Society Asthma: A Historical Perspective The Evolution of the Understanding of Asthma as an Allergic Disorder House Dust Mite as Allergen The Origins of Allergic Asthma Environmental Influences The Hygiene Hypothesis Respiratory Viruses and Asthma Modeling Virus-Allergen Interactions Rational and Goal of this Thesis Work Chapter 2: Acute, but not Resolved, Influenza A Infection Enhances Susceptibility to House Dust Mite Induced Allergic Disease………………...................................................................24-41 Chapter 3: Shifting of Immune Responsiveness to House Dust Mite by Influenza A Infection: Genomic Insights.……………………......42-80 Chapter 4: Influenza A Facilitates Sensitization to House Dust Mite in Infant Mice Leading to and Asthma Phenotype in Adulthood…………………………………………………….81-101 Chapter 5: Discussion……………………………………………………...102-118 References: (for Chapters 1&5)……………………………………………119-139 Appendix I: Impact of IL-6 Blockade on HDM-Induced Inflammation…..140-142 Appendix II: Copyright Permission to Reprint Published Manuscripts………..143 vii LIST OF ABBREVIATIONS AHR airway hyperresponsiveness IL interleukin Ab antibody Ig immunoglobulin Ag antigen N neuraminidase APC antigen presenting cell OVA ovalbumin CLR C-type lectin receptors PAMP pathogen activated molecular patterns DC dendritic cells PRR pattern recognition receptors DAMP damage associated molecular p.i. post infection pattern EC epithelial cells RSV respiratory syncytial virus HDM house dust mite hRV human rhinovirus FcεR1 high affinity IgE receptor Th T helper GM-CSF granulocyte-macrophage TLR toll-like receptors colony-stimulating factor H hemagglutinin TSLP thymic stromal lymphopoietin INF interferon TNF-α tumor necrosis factor-α viii PREFACE The research described in Chapters 2-4 of this “sandwich thesis” is presented as three independent but thematically related bodies of work that, as of April 2012, have all been published. The research performed in each manuscript required a collaborative effort with several colleagues, resulting in multiple authors. CHAPTER 2 Al-Garawi AA, Fattouh R, Walker TD, Jamula EB, Botelho F, Goncharova S, Reed J, Stampfli MR, O'Byrne PM, Coyle AJ, Jordana M. Acute, but not resolved, influenza A infection enhances susceptibility to house dust mite- induced allergic disease. J Immunol. 2009 Mar 1; 182(5): 3095-104. This study was conducted over the period June 2006-August 2008. I, as the author of this doctoral thesis, designed and performed all the experiments, analyzed and interpreted the data and wrote the manuscript. Experimental assistance was provided by R. Fattouh (graduate student), T.D. Walker (technician), F. Botelho (post-doctoral fellow) and S. Goncharova (technician). E.B. Jamula was an undergraduate student who worked on this project under my supervision. J. Reed (MedImmune collaborator) kindly provided the influenza A viral strain PR8/38. Drs. M.R. Stampfli, P.M. O’Byrne and A.J. Coyle provided valuable scientific input. CHAPTER 3 Al-Garawi A*, Hussain M*, Ilieva D, Humbles AA, Kolbeck R, Stampfli MR, O’Byrne PM, Coyle AJ and Jordana M. Shifting of immune responsiveness to house dust mite by influenza A infection: Genomic insights. J Immunol. 2012 Jan 15;188(2):832-43. ix This study was conducted from Dec 2008-February 2010. This manuscript was an equal contribution (*). I designed and performed all in vivo experiments, guided data analysis and wrote the manuscript. Mainul Hussain analyzed the data and also wrote the manuscript. Experimental assistance was provided by D. Ilieva (post-doctoral fellow). Drs. A. Humbles and R. Kolbeck (MedImmune collaborators), M. Stampfli, P.M. O’Byrne and A.J. Coyle critically appraised the manuscript. CHAPTER 4 Al-Garawi A, Fattouh R, Botelho F, Walker TD, Goncharova S, Moore CL, Mori M, Erjefalt JS, Chu DK, Humbles AA, Kolbeck R, Stampfli MR, O'Byrne PM, Coyle AJ, Jordana M. Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood. Mucosal Immunol. 2011 Nov; 4(6): 682-94. This study was conducted from May 2008-January 2011. I designed and performed all the experiments, analyzed and interpreted the data and wrote the manuscript. Experimental assistance was provided by R. Fattouh, F. Botelho, T.D. Walker, S. Goncharova and C.L. Moore (undergraduate student) and D. Chu (graduate student). M. Mori and Dr. J.S. Erjefalt (both Lund University collaborators) provided analysis on parenchymal remodeling and critically appraised the manuscript. Drs. A. Humbles and R. Kolbeck critically appraised the manuscript. M. Stampfli, P.M. O’Byrne and A.J. Coyle contributed valuable scientific input and critically appraised the manuscript. x Ph.D. Thesis – A. Al-Garawi McMaster University – Medical Sciences Chapter 1 INTRODUCTION 1 Ph.D. Thesis – A. Al-Garawi McMaster University – Medical Sciences PREFACE : ASTHMA AND ITS IMPACT ON SOCIETY Asthma is a chronic immune-inflammatory disease of the airways, characterized by reversible airflow obstruction and airway hyperresponsiveness (AHR), and associated with the development of airway remodeling. Following exposure to a wide range of triggers, the airways of asthmatic individuals contract excessively resulting in breathlessness, wheezing, chest tightness and coughing. The disease can range from mild, occasional symptoms to severe, persistent symptoms with considerable morbidity and mortality rates. Worldwide, it is estimated that asthma affects over 300 million people and results in approximately 250,000 deaths (1, 2). Although asthma can develop at any age, it is most frequently diagnosed in young children and, in fact, is the most prevalent chronic disease during childhood (1). Once diagnosed, asthma is generally a lifelong affliction with
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