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Adenovirus Vectors As Potent Adjuvants in Vaccine Development Loyola University Chicago Loyola eCommons Dissertations Theses and Dissertations 2014 Adenovirus Vectors as Potent Adjuvants in Vaccine Development Kathleen Ann Mcguire Loyola University Chicago Follow this and additional works at: https://ecommons.luc.edu/luc_diss Part of the Virology Commons Recommended Citation Mcguire, Kathleen Ann, "Adenovirus Vectors as Potent Adjuvants in Vaccine Development" (2014). Dissertations. 905. https://ecommons.luc.edu/luc_diss/905 This Dissertation is brought to you for free and open access by the Theses and Dissertations at Loyola eCommons. It has been accepted for inclusion in Dissertations by an authorized administrator of Loyola eCommons. For more information, please contact [email protected]. This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. Copyright © 2014 Kathleen Ann Mcguire LOYOLA UNIVERSITY CHICAGO ADENOVIRUS VECTORS AS POTENT ADJUVANTS IN VACCINE DEVELOPMENT A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL IN CANDIDACY FOR THE DEGREE OF DOCTOR OF PHILOSOPHY PROGRAM IN MICROBIOLOGY AND IMMUNOLOGY BY KATHLEEN A. MCGUIRE CHICAGO, IL MAY 2014 Copyright by Kathleen A. McGuire, 2014 All rights reserved. ACKNOWLEDGEMENTS I want to thank my mentor, Dr. Chris Wiethoff, for his guidance throughout this process. Chris has taught me how to think critically, work independently, and has pushed me to reach my fullest potential. I would like to thank my committee chair, Dr. Ed Campbell, and the rest of my committee members: Dr. Knight, Dr. Gallagher and Dr. Zeleznik-Le. All of you have been incredibly influential in this process. I appreciate all of your feedback and suggestions. I want to thank the rest of the Microbiology and Immunology Department. I have appreciated the collegial work environment and the supportive group of faculty, staff and students. My friends and fellow lab members have made this experience incredibly fun. Chris sets the tone in the lab. He is invested in each student’s progress and runs a focused, hard-working lab while maintaining a light-hearted atmosphere. Thanks to all my lab mates and a special thanks to Shauna who has been a supportive friend as well as a lab mate. Thanks to my friends for making life in Chicago one of the best experiences of my life. I want to thank my family. To my brothers, Michael and Danny, I am proud to call you guys my brothers. Thanks for always looking out for your big sister. To my Mom and Dad, your unyielding support and love has always been exceptional. Your work ethic and drive have served as a model for my own life goals. Mom, you are the strongest person I know. You face every hardship with such grace and still manage to take care of everyone else so thanks to my family for everything. iii TABLE OF CONTENTS ACKNOWLEDGMENTS iii LIST OF TABLES vi LIST OF FIGURES vii ABSTRACT ix CHAPTER I: INTRODUCTION 1 Vaccines 3 Adenoviruses 7 Innate Immune Response to Adenovirus 7 ROS as an Innate Immune Signal 12 Cellular Mediators of the Innate Immune Response to Adenovirus 18 Innate Immunity to Adenovirus is crucial to activation of the adaptive response 21 Adaptive Immune Response 22 Adenovirus as a Vaccine Vector 30 Malaria Pathogenesis and Current Vaccine Approaches 34 CHAPTER II: MATERIALS AND EXPERIMENTAL METHODS 44 Cell lines and Culture 44 Stable cell lines 44 Virus Generation 45 Virus Preparation 47 Pfs25 expression from Ad5-pfs25 48 Reagents and Antibodies 49 Quantification of IL-1β and TNF-α secretion by ELISA 49 ROS Assay 50 Western Blot Analysis 50 qPCR for gp91phox Levels 51 Measurement of Cytosolic Cathepsin B and Cytochrome C 52 Assessment of Mitochondrial Membrane Potential 53 Mice and Immunizations 54 Determination of Pfs25-specific Antibody Titer and IgG Subclass Production 55 Determining the Relative Affinity of Pfs25-specific Serum Antibodies 55 B cell ELISPOTs 56 Ex Vivo Splenocyte Stimulation and Cytokine Production 57 Parasite Binding Assays 57 Standard Membrane Feeding Assays 58 iv Statistics 59 CHAPTER III: RESULTS 60 Investigating the role of reactive oxygen species in the proinflammatory response to adenovirus infection 60 Characterizing the antibody response to Pfs25 following vaccination with Ad5 expressing pfs25 90 Characterizing the antibody response to Pfs25 following heterologous prime-boost vaccination with Ad5-pfs25 followed by Pfs25-alum or homologous prime-boost with Pfs25-alum 105 Characterizing the antibody response to Pfs25 following boost with Ad5 containing capsid-displayed Pfs25 B cell epitopes 111 Determining the parasite-binding and transmission-blocking functions of Pfs25-specific antibodies generated by heterologous prime-boost vaccination with Ad5-pfs25 followed by boost with Ad5 containing capsid-displayed Pfs25 B cell epitopes 120 Determining the effect of pre-existing immunity on the antibody response to Pfs25 following vaccination with Ad5 containing capsid-displayed Pfs25 B cell epitopes 125 CHAPTER IV: DISCUSSION 130 ROS Play a Key Role in the Innate Immune Response to Adenovirus type 5 Infection 134 Ad5 induces ROS from the Mitochondria 136 Ad5-mediated Membrane Rupture is Required for the Generation of ROS 138 Cathepsin Activity Facilitates Mitochondrial Membrane Destabilization 140 The Natural Adjuvant Properties of Ad5 Vaccine Vectors can be Exploited to Generate Improved Transmission-blocking Vaccines Against Malaria 143 Vaccination with either Ad5 Expressing Pfs25 or Pfs25-alum does not elicit Pfs25-specific IFNγ-producing T cells 147 Vaccination with Ad5 Expressing pfs25 generates antibody-secreting cells in the bone marrow 150 Heterologous Prime-boost Vaccination with Ad5-pfs25 Followed by Pfs25-alum a More Robust Anti-Pfs25 Antibody Response than Homologous Prime-boost With Pfs25-alum 151 Boost Vaccination with Novel Adenovirus-vectored Vaccines Displaying Pfs25 B Cell Epitopes Enhances the Pfs25-specific Antibody Response 153 Ad5-HVR-pfs25 Boost Generates a Robust Pfs25-specific Antibody Response 155 Ad5-vectored Prime-boost Vaccinations Generate Pfs25-specific Antibodies that Bind Mosquito Stage Plasmodium falciparum Gametes and Block Transmission 157 Pre-existing Immunity does not Affect the Immune Response to Capsid- displayed Antigens upon Primary Immunization with Ad5-HVR-pfs25 161 REFERENCES 163 v VITA 185 vi LIST OF TABLES Table 1. Primer Sequences for Recombineering 47 vii LIST OF FIGURES Figure 1. Adenovirus Capsid 6 Figure 2. Innate Immune Activation following Adenovirus Infection 13 Figure 3. Model of Potential Sources of ROS upon Adenovirus Infection 15 Figure 4. Malaria Pathogenesis 36 Figure 5. Pfs25 Structure 40 Figure 6. Role of NLRP3, Caspase-1 and ROS in Ad5-induced IL-1β release 63 Figure 7. Ad5-induced ROS production and the role of ROS in Ad5-induced TNFα secretion 70 Figure 8. ROS production in response to Ad5 infection in the presence or absence of TLR9 knockdown 72 Figure 9. ROS production in response to Ad5 in the presence or absence of gp91phox (Nox2) knockdown 75 Figure 10. Ad5-induced ROS production and IL-1b Release in the presence or absence of bcl-2 overexpression 78 Figure 11. Proposed Mechanism of Ad5-Induced ROS 80 Figure 12. Cellular Localization of Cathepsin following Ad5 treatment 84 Figure 13. Mitochondrial membrane destabilization upon Ad5 infection in the presence or absence of the cathepsin B inhibitor Ca074me 87 Figure 14. Ad5-induced ROS in the presence of Ca074me 89 Figure 15. Pfs25 expression from a transgene within the Ad5 genome 95 Figure 16. Pfs25-specific serum antibody response upon primary immunization with an Ad vector expressing Pfs25 100 viii Figure 17. Antibody-secreting cells from the spleen and bone marrow following Ad5-pfs25 or Pfs25-alum vaccination 103 Figure 18. T cell activation following Ad5-pfs25 primary vaccination 106 Figure 19. Pfs25-specific serum antibody response upon heterologous prime-boost with Ad5-pfs25 followed by Pfs25-alum or homologous prime-boost with Pfs25-alum 110 Figure 20. Pfs25 epitope expression within Ad5 Hexon 113 Figure 21. Pfs25-specific serum antibody response upon primary immunization with Pfs25-alum and boost with Ad containing capsid-displayed Pfs25 B cell epitopes 116 Figure 22. Pfs25-specific serum antibody response upon heterologous prime-boost Ad5-pfs25 followed by Ad5-HVR-pfs25 boost 122 Figure 23. P. falciparum load in Anopheles mosquitoes in the presence of vaccine serum 124 Figure 24. Ad12 cross-reactivity with Ad5 pre-existing immunity 127 Figure 25. Pfs25-specific serum antibody response upon primary immunization in the presence of pre-existing immunity 129 ix ABSTRACT Due to their ability to activate the immune system, replication-defective Adenoviruses (Ad) are potential vaccine vectors for several pathogens. The rapid proinflammatory response generated by Ad is key to the ability of these vectors to generate a response to a target vaccine antigen. We found that reactive oxygen species (ROS) are an important signal in the proinflammatory response to Ad. We identified that serotype 5 adenovirus (Ad5) elicits ROS by inducing mitochondrial membrane damage, a process that is dependent on endosomal membrane rupture and Cathepsin release. Our studies demonstrated that mitochondrial damage contributes to NLRP3 inflammasome- and NFκB-dependent innate immune activation upon Ad infection. This ROS-dependent inflammatory response likely contributes to the adaptive immune response by supporting DC maturation and activation, lymphocyte recruitment to the site of vaccination, and cytokine production influencing B and T
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