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A Thesis Entitled Beta-Defensin 3-Mediated Regulation Of A Thesis entitled Beta-Defensin 3-Mediated Regulation of Transcriptional Changes During Oropharyngeal Candidiasis by Cole Jacob White Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Biomedical Science: Bioinformatics, Proteomics and Genomics Dr. Heather Conti, Committee Chair Dr. Alexei Fedorov, Committee Member Dr. Sadik Khuder, Committee Member Dr. Amanda Bryant-Friedrich, Dean College of Graduate Studies The University of Toledo August 2018 Copyright 2018, Cole Jacob White This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Beta-Defensin 3-Mediated Regulation of Transcriptional Changes During Oropharyngeal Candidiasis by Cole Jacob White Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Biomedical Science: Bioinformatics, Proteomics and Genomics The University of Toledo August 2018 Oropharyngeal candidiasis (OPC) is a fungal infection of the oral cavity caused by a human commensal fungus called Candida albicans. Even though C. albicans is a commensal, it can become pathogenic in immunocompromised patients. IL-17-mediated antifungal immunity has been implicated as the major pathway for fungal defense in the oral cavity. The IL-17 pathway has been found to regulate the release of antimicrobial peptides (AMPs) downstream, including murine β-defensin 3 (mBD3). Murine β-defensin 3 is an antimicrobial peptide involved in the protection of the oral mucosa against pathogens. Murine BD3 can protect the oral mucosa through its direct antimicrobial activity, but it has also been found to have chemotactic properties as well. The human homolog of mBD3, human β-defensin 2 (hBD2), has been found to bind CCR6. CCR6 is found on the surface of cells like memory T-cells, dendritic cells (DCs), Th17 cells, and Treg cells. Studies have shown that hBD2 binding to CCR6 on the surface of memory T-cells and DC’s can induce chemotaxis, and other studies have suggested the same could be true for Th17 cells and Treg cells. iii The goal of this experiment was to study the chemotactic ability of mBD3 via RNA-sequencing to explore how the presence/absence of Defb3 leads to changes in transcriptional regulation while in the presence/absence of an OPC infection. The RNA- sequencing results reveal that there are very few differences in transcript expression between wild-type mice and Defb3 knockout mice. One difference in transcript expression between Defb3 knockout mice and WT mice is found in Sycp1. Sycp1 is expressed at higher levels in Defb3 knockout infected mice when compared with WT infected mice and Defb3 knockout sham mice when compared to WT sham mice. The DNA-binding ability of Sycp1 makes it an interesting candidate for future studies. iv To my family, thank you for your love and support throughout this journey. Without you, I wouldn’t be where I am today. May this be the first of many written theses… And to my loving fiancé, thank you for all of your support. I can’t wait to start the next leg of our journey in medical school together. Go Bobcats! v Acknowledgements I would like to thank my advisor, Dr. Heather Conti for her guidance and support over the last few years. Without your willingness to accept me as an undergraduate researcher, I wouldn’t be where I am today. Thank you for your guidance as I navigated my path from undergrad, to graduate school, and into medical school. Thank you to the other members of my thesis committee, Dr. Alexei Fedorov and Dr. Sadik Khuder, for your commitment and your insight as a prepared for my defense. I would like to thank the fellow graduate students/laboratory tech in the Conti Lab: Dylan Launder, Katie McKeone, Jackie Kratch, and Nathan Schmidt. Thank you for the stimulating conversations, the light-hearted laughs, and the fun times. Best of luck to all of you in your future endeavors. Finally, to the rest of the Conti Lab, thank you for creating a welcoming environment. It’s been fun… vi Table of Contents Abstract .............................................................................................................................. iii Acknowledgements ............................................................................................................ vi Table of Contents .............................................................................................................. vii List of Tables ................................................................................................................... ix List of Figures ......................................................................................................................x List of Abbreviations ......................................................................................................... xi List of Symbols ................................................................................................................ xiii 1 Literature Review.....................................................................................................1 1.1 Candida albicans and Oropharyngeal Candidiasis ...........................................1 1.2 Pattern Recognition of Candida albicans .........................................................2 1.3 Pathogenicity of Candida albicans ...................................................................4 1.4 IL-17-Mediated Antifungal Immunity ..............................................................5 1.5 Murine Beta-Defensin 3 ....................................................................................7 1.6 Mechanisms of Beta-Defensin 3 Antimicrobial Activity .................................9 1.7 Inbred Mouse Model .......................................................................................11 1.8 RNA-sequencing .............................................................................................12 2 Materials and Methods ...........................................................................................15 2.1 Preparation of Candida albicans Culture .......................................................15 2.2 Induction of Oropharyngeal Candidiasis ........................................................15 vii 2.3 Harvesting Tongue Tissue ..............................................................................16 2.4 Quantification of Fungal Burden ....................................................................16 2.5 Experimental Mice ..........................................................................................17 2.6 RNA-Sequencing ............................................................................................17 2.7 Processing of RNA-Sequencing Results .........................................................18 3 Results…………… ................................................................................................20 3.1 Experimental Design .......................................................................................20 3.2 Wild-Type Infected versus Wild-Type Sham .................................................22 3.3 Defb3 Knockout Infected versus Wild-Type Infected ....................................23 3.4 Defb3 Knockout Sham versus Wild-Type Sham ............................................26 3.5 Defb3 Knockout Infected versus Defb3 Knockout Sham ...............................27 4 Discussion……….. ................................................................................................30 4.1 Wild-Type Infected versus Wild-Type Sham Results ....................................30 4.2 Increased Sycp1 Expression in Defb3 Knockout Mice ...................................32 4.3 Defb3 Knockout Sham versus Wild-Type Sham Results ...............................32 4.4 Defb3 Knockout Infected versus Defb3 Knockout Sham ...............................33 4.5 Conclusions .....................................................................................................34 References ..........................................................................................................................36 A Code .......................................................................................................................42 B Appendix Tables ....................................................................................................70 C Bioanalyzer Results .............................................................................................116 viii List of Tables 3.1 WT Infected vs. WT Sham Top 35 Positive Results .............................................24 3.2 WT Infected vs. WT Sham Top 35 Negative Results ............................................25 3.3 Defb3 Knockout Infected vs. WT Infected Results ...............................................26 3.4 Defb3 Knockout Sham vs. WT Sham Results .......................................................27 3.5 Defb3 KO Infected vs. Defb3 KO Sham Top 35 Positive Results.........................28 3.6 Defb3 KO Infected vs. Defb3 KO Sham Top 35 Negative Results .......................29 B.1 WT Infected vs. WT Sham Full Results ................................................................70 B.2 Defb3 Knockout Infected vs. Defb3 Knockout Sham Full Results .....................100 C.3 Key to Differentiate the Sample Names in Figure C-1 ........................................117 ix List of Figures 3-1 Fungal Burden of the IL-17RA Knockout Mice (Positive
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