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Immunosenescence and Exercise-Mediated Modulation of the Innate Immune Response to Influenza Infection in Mice Shibani Naik Iowa State University

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Immunosenescence and Exercise-Mediated Modulation of the Innate Immune Response to Influenza Infection in Mice Shibani Naik Iowa State University Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2013 Immunosenescence and exercise-mediated modulation of the innate immune response to Influenza infection in mice Shibani Naik Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Allergy and Immunology Commons, Family, Life Course, and Society Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons, and the Physical Therapy Commons Recommended Citation Naik, Shibani, "Immunosenescence and exercise-mediated modulation of the innate immune response to Influenza infection in mice" (2013). Graduate Theses and Dissertations. 13342. https://lib.dr.iastate.edu/etd/13342 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Immunosenescence and exercise-mediated modulation of the innate immune response to Influenza infection in mice by Shibani Naik A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Immunobiology Program of Study Committee: Marian Kohut, Major Professor Mark Ackermann Joan Cunnick Peter Nara Daniel Nettleton Iowa State University Ames, Iowa 2013 Copyright © Shibani Naik, 2013. All rights reserved. ii TABLE OF CONTENTS ABSTRACT iv CHAPTER 1. GENERAL INTRODUCTION Introduction to the Dissertation 01 Literature Review: Influenza viral infection 01 Immune response to influenza infection 08 Immunosenescence 25 Exercise and the Immune System 37 CHAPTER 2. AGE IMPAIRS INNATE IMMUNE RESPONSE TO INFLUENZA INFECTION IN MICE. Abstract 40 Introduction 41 Materials and Methods 44 Results 47 Discussion 53 Figures 57 References 86 CHAPTER 3. MODERATE EXERCISE REDUCES VIRAL LOAD AND ALTERS INNATE IMMUNE RESPONSE TO INFLUENZA INFECTION IN AGED MICE. Abstract 90 Introduction 91 Materials and Methods 94 Results 99 Discussion 100 Figures 104 References 119 iii CHAPTER 4. ACUTE EXERCISE INDUCES A STRESS RESPONSE IN LUNGS OF MICE. Abstract 124 Introduction 125 Materials and Methods 127 Results 129 Discussion 132 Figures 136 References 149 CHAPTER 5. CONCLUSIONS FOR THE DISSERTATION 152 References 156 REFERENCES FOR THE DISSERTATION 158 APPENDIX 177 ACKNOWLEDGEMENTS 186 iv ABSTRACT Influenza virus is a negative sense, single stranded RNA virus that can cause severe respiratory tract infections in humans (along with other host animals such as horses, swine and poultry). Certain populations such as very young children, aged individuals, pregnant women and immunosuppressed individuals are more susceptible to influenza infections. One reason for the increased susceptibility to infection in the aged is a decreased efficacy of the seasonal influenza vaccine. As this particular section of our population continues to increase worldwide, research to improve vaccine efficacy is expanding along with efforts to identify lifestyle changes and interventions that can improve the immune response to vaccination. For these purposes, it is important to understand the mechanism by which age affects the immune response. Multiple age- related defects in T-cell or B-cell response to influenza infection have been well documented, but the impact of age on innate host defense to influenza is not well-characterized. Defects of the early innate host antiviral pathways have not been studied in depth and could impact early host defense as well as appropriate activation of adaptive immunity. The aim of the study conducted in chapter 2 was to identify age-associated alterations of innate recognition/response to influenza virus. The results identified an impairment of innate defense proteins and Toll Like Receptor signaling molecules in lungs of healthy old mice compared to young mice. The study also confirmed the presence of a chronic low level inflammation in the lungs usually systemically associated with aging. Mice infected with influenza virus elicited an impaired and possibly delayed anti-viral response to the virus. It has been suggested that exercise can modulate the immune response to various respiratory pathogens. Physical activity may be beneficial for the immune response to pathogens v and infections in aged immune systems by decreasing morbidity and mortality. In chapter 3, we studied the potential impact of exercise on innate immune pathogen recognition and anti-viral responses. We used a model of chronic, regular moderate exercise in comparison to no exercise to assess alterations in the immune response to influenza virus infection. An exercise-associated reduction of lung viral load was observed in aged exercised-treated mice that were infected with influenza virus as compared to aged non-exercised mice. The results from this chapter indicated that early host innate defenses were altered by exercise training and may lead to the decreased viral load early during the course of influenza infection. In chapter 4, the acute effects of a single session of exercise were studied in lungs of young mice. This was done in order to identify an effect of exercise on the activation of stress or host defense pathways given that the response of lung tissue to exercise is not well known, as compared to the effect of exercise on other tissues such as cardiac or skeletal muscle. Activation of stress response or altered cellular defense pathways and immune cell populations could affect the lung response to a pathogen such as influenza virus. In our results we discovered that acute exercise resulted in heat shock protein response as well as activation of several genes associated with regulation of inflammation. The effects of chronic exercise on the same stress response was also studied, resulting in a down-regulation of heat shock proteins, and no change in expression of genes associated with apoptosis or inflammation. Exercise training may cause a shift of CD45 positive leukocytes from the BAL into the lungs as the CD45+ population decreased in the BAL, but increased in the lung. Taken together, these changes suggest that exercise training may promote an anti-inflammatory environment in the lung. We speculate that exercise training may cause the lung tissue to adapt to stress and downregulate the heat shock response and any inflammation caused due to exercise. A shift in immune cells from BALF to lungs may explain vi our previous findings of reduced viral titer and decreased inflammation with influenza infection in exercise trained mice. 1 CHAPTER 1 GENERAL INTRODUCTION Introduction to the dissertation Organization of the Dissertation This dissertation contains the experimental data and results obtained by the author during her Ph.D. study under the supervision of her major professor Dr. Marian L. Kohut at Iowa State University, Immunobiology Interdepartmental Program. The document contains manuscripts that are being prepared for submission to peer- reviewed journals. The dissertation contains a total of five chapters including a general introduction, three research papers, and a general conclusion that discusses the overall findings from the dissertation, followed by acknowledgements. The figures are provided directly following each chapter, followed by the references. The General Introduction (Chapter I) to the dissertation begins with briefly the background information on the lifecycle of influenza A viruses and the host immune response to the virus. This is followed by the current status of knowledge and literature review on aging immunology research and exercise immunology. Chapter 2 focuses primarily on aging and the innate immune response, while chapters 3 and 4 focus on exercise immunology in the old and the young respectively. This is followed by the conclusions and summary of the findings of the dissertation, presented in chapter 5. The references that are used in the Introduction and literature review are provided, followed by the acknowledgements at the end. Influenza virus Infection The influenza virus is part of the Orthomyxoviridae family of viruses. These are negative sense, single stranded RNA viruses and include the thogotovirus and isavirus, along with the 2 three genera of influenza viruses, types A, B and C. Influenza A viruses are the causative agent of most severe respiratory tract infections. The symptoms of influenza viral infection may include fever, chills, cough, sore throat, runny or stuffy nose, pronounced fatigue, and less often nausea, vomiting and/or diarrhea. Some infected people may have no symptoms but may shed virus for up to a week. Severe cases of infection may require hospitalization and can be fatal, primarily because of damage caused by the immune response in the lung microenvironment. Influenza B viruses cause the same spectrum of disease as influenza A. However, influenza B viruses do not cause pandemics, possibly because of the limited hosts (humans and seals). Influenza C virus causes mild upper respiratory tract illness, and nearly all adults have been infected with influenza C virus (217). Vaccines for influenza infection are available and contain two strains of Influenza A and one Influenza B strain. There are two types of influenza vaccine – the trivalent inactivated vaccine containing killed virus, and the live, attenuated intranasal influenza vaccine.
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