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Identification of Cytokine Profiles Associated with Endometrial Chlamydia Infection

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Identification of Cytokine Profiles Associated with Endometrial Chlamydia Infection IDENTIFICATION OF CYTOKINE PROFILES ASSOCIATED WITH ENDOMETRIAL CHLAMYDIA INFECTION De’Ashia Elizabeth Lee A thesis submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Master of Science in the Department of Microbiology and Immunology in the School of Medicine. Chapel Hill 2018 Approved by: Toni Darville Nilu Goonetilleke Jason Whitmire Barbara Salvodo © 2018 De’Ashia Elizabeth Lee ALL RIGHTS RESERVED ii ABSTRACT De’Ashia Elizabeth Lee: Identification of Cytokine Profiles Associated with Endometrial Chlamydia Infection (Under the direction of Toni Darville and Nilu Goonetilleke) Chlamydia trachomatis (CT) infection can lead to reproductive tract morbidities when it ascends to the upper genital tract of women, and repeated infections worsen disease. Cervical cytokines associated with disease or infection susceptibility in women are unknown. Forty-eight cytokines were measured in cervical secretions of 160 women with CT infection, 68 who had endometrial infection, and 92 with cervical infection only. Participants were monitored for repeat CT infections over the following year. Multivariable stepwise regression examined whether cytokines were associated with endometrial infection at the enrollment visit or reinfection. IL-16, was associated with decreased risk of endometrial infection while CXCL10, CXCL13, and TNFα, were associated with increased risk of endometrial infection. Although we did not identify cytokines significantly associated with an altered risk of repeat infection, VEGF, a T cell chemokine, and IL-14, a B cell chemokine, were associated with decreased and increased risk of reinfection by univariable analysis, respectively. iii ACKNOWLEDGEMENTS To my family and friends, thank you for all the unconditional love and support throughout my life. Your unwavering, selfless support offers me endless motivation to overcome any obstacle. In your own unique ways, each one of you has taught me that to an unstoppable force, there is no immovable object. To my mentors, past and present, thank you for your guidance and mentorship. I appreciate the dedication and support that you all have offered me throughout the years. To Toni and Nilu, thank you for the opportunity to become a member of your labs. I have learned so much from the both of you, and I am sure these lessons will serve me well in the future. To Jason and Barbara, thank you for the generosity, feedback, and willingness to serve on my committee. To Ashalla, Kim, and Jessica, thank you for listening, understanding, motivating, and supporting me throughout the years. This would not be possible without you! To Bob, thank you for your dedication to the students, I appreciate all that you have done and continue to do. I would like to thank all the women who participated in TRAC. Without your involvement and cooperation, I would not have been able to conduct this analysis. Additionally, I would also like to thank the members of the Immunology unit of the Duke Regional Biocontainment Laboratory for their assistance in running all the panels. Finally, I would like to thank the biostatisticians on this project for their excellent guidance and support during this process. Jing, Wujuan, and Li, your assistance has been invaluable. I could not have done this without you! iv TABLE OF CONTENTS LIST OF TABLES ........................................................................................................................ vii LIST OF FIGURES ..................................................................................................................... viii LIST OF ABBREVIATIONS ........................................................................................................ ix Chapter 1: History ........................................................................................................................... 1 Lifecycle ......................................................................................................................................... 2 Serovar classifications .................................................................................................................... 2 Clinical manifestations ................................................................................................................... 3 Diagnosis ........................................................................................................................................ 3 Epidemiology .................................................................................................................................. 4 Pelvic Inflammatory Disease .......................................................................................................... 4 Current treatment options ............................................................................................................... 6 Innate immunity .............................................................................................................................. 6 Toll-like receptors ....................................................................................................................... 6 Chlamydial plasmid..................................................................................................................... 7 Matrix metalloproteinases ........................................................................................................... 7 Neutrophils .................................................................................................................................. 8 Cytokines and Chemokines ......................................................................................................... 9 IL-1 .......................................................................................................................................... 9 TNFα ...................................................................................................................................... 10 IL-17A ................................................................................................................................... 11 Chemokines ........................................................................................................................... 12 Adaptive immunity ....................................................................................................................... 13 Humoral immunity .................................................................................................................... 13 IgG in human studies ............................................................................................................. 14 v IgA in mouse models ............................................................................................................. 14 IgA in human studies ............................................................................................................. 15 Cell-mediated immunity ............................................................................................................ 15 CD4+ T cells ............................................................................................................................. 15 CD4+ T cells and protection in mice ..................................................................................... 15 CD4+ T cells and protection in humans ................................................................................ 16 CD4+ T cells and pathology in mice ..................................................................................... 17 CD4+ T cells and pathology in humans ................................................................................ 18 CD8+ T cells ............................................................................................................................. 18 CD8+ T cells and protection in mice ..................................................................................... 18 CD8+ T cells and protection in humans ................................................................................ 19 CD8+ T cells and pathology in mice ..................................................................................... 20 CD8+ T cells and pathology in humans ................................................................................ 21 Summary of immune responses associated with chlamydia-induced pathology ...................... 22 Current study ................................................................................................................................. 24 INTRODUCTION ........................................................................................................................ 24 METHODS ................................................................................................................................... 27 Study population ....................................................................................................................... 27 Definition of clinical and microbiological subgroups ............................................................... 28 Quantification of cytokines in cervical secretions .................................................................... 29 Statistical Analysis .................................................................................................................... 31 Preliminary statistical analysis .............................................................................................
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