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University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 6-2020 Understanding Human Astrovirus from Pathogenesis to Treatment Virginia Hargest University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Diseases Commons, Medical Sciences Commons, and the Viruses Commons Recommended Citation Hargest, Virginia (0000-0003-3883-1232), "Understanding Human Astrovirus from Pathogenesis to Treatment" (2020). Theses and Dissertations (ETD). Paper 523. http://dx.doi.org/10.21007/ etd.cghs.2020.0507. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. Understanding Human Astrovirus from Pathogenesis to Treatment Abstract While human astroviruses (HAstV) were discovered nearly 45 years ago, these small positive-sense RNA viruses remain critically understudied. These studies provide fundamental new research on astrovirus pathogenesis and disruption of the gut epithelium by induction of epithelial-mesenchymal transition (EMT) following astrovirus infection. Here we characterize HAstV-induced EMT as an upregulation of SNAI1 and VIM with a down regulation of CDH1 and OCLN, loss of cell-cell junctions most notably at 18 hours post-infection (hpi), and loss of cellular polarity by 24 hpi. While active transforming growth factor- (TGF-) increases during HAstV infection, inhibition of TGF- signaling does not hinder EMT induction. However, HAstV-induced EMT does require active viral replication. These are among the first studies describing the induction of EMT by a non-oncogenic virus and provides an exciting opportunity to understand EMT induction independent of cancer. Our findings likely extend beyond astrovirus to other viruses and may shed light on novel ways pathogens can circumvent the barriers meant to protect against them. Crossing these barriers can lead to systemic and even fatal infections. Astroviruses can be especially problematic in immunocompromised individuals and infants where the virus has been associated with necrotizing enterocolitis, severe and persistent diarrhea, and even encephalitis and meningitis. Using our novel tools and models, we demonstrate that the FDA-approved broad-spectrum anti-infective drug nitazoxanide (NTZ) blocks astrovirus replication in vitro with a 50% effective concentration (EC50) of approximately 1.47μM. It can be administered up to 8 hours post-infection and is effective against multiple human astrovirus serotypes including clinical isolates. Most importantly, NTZ reduces viral shed in vivo, exhibiting its potential as a future clinical therapeutic. Overall, these studies will further our understanding of astrovirus pathogenesis leading to the development of therapeutic options for vulnerable populations. Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Biomedical Sciences Research Advisor Stacey Schultz-Cherry, PhD Keywords Cellular biology, virology, microbiology Subject Categories Diseases | Medical Sciences | Medicine and Health Sciences | Viruses This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/523 UNIVERSITY OF TENNESSEE HEALTH SCIENCE CENTER DOCTOR OF PHILOSOPHY DISSERTATION Understanding Human Astrovirus from Pathogenesis to Treatment Author: Advisor: Virginia Hargest Stacey Schultz-Cherry, PhD A Dissertation Presented for The Graduate Studies Council of The University of Tennessee Health Science Center in Partial Fulfillment of the Requirements for the Doctor of Philosophy degree from The University of Tennessee in Biomedical Sciences: Microbiology, Immunology, and Biochemistry College of Graduate Health Sciences June 2020 Chapters 3 and 5 © 2020 by American Society for Microbiology. All other material © 2020 by Virginia Hargest. All rights reserved. ii DEDICATION To my amazing fiancé Winter, my Mom and Dad, and Jessie, for their constant support and encouragement. I love you and I could not have gotten here without you. iii ACKNOWLEDGEMENTS First and foremost, I want to thank my mentor Dr. Stacey Schultz-Cherry. Stacey has allowed me to grow as a scientist and encouraged me along the way. She has taught me how to think critically, how to perform the right tests to answer the questions my project has raised, and has made me a more confident scientist. She gave me enough freedom to study what I was curious about, but reigned me back in when I would get stuck down a rabbit hole. Stacey has been there for the lows of multiple hypotheses being proven wrong and the highs of my first first-author publication and all the times in between. She is my role model for what a strong woman in science should be and I owe her everything for the scientist I have become. I also would like to thank my committee members Dr. Mike Whitt, Dr. RK Rao, Dr. Jason Rosch, and especially Dr. Carolyn Coyne, for serving as an external member. I appreciate their time, commitment, and for their helpful guidance through my graduate career. Finally, as every graduate student can attest, a majority of what you learn during your graduate studies comes from those you interact with on a daily basis. With that said, I want to thank the many members, past and present, of the Schultz-Cherry Lab. I want to especially thank Victoria Meliopoulos, Pam Freiden, Val Cortez, Bekah Honce, and Cydney Johnson. Whether it be teaching me a new technique, answering questions, helping with figure design, editing manuscripts, or just keeping me (mostly) sane, each of them has contributed to my success and I thank them for it. iv ABSTRACT While human astroviruses (HAstV) were discovered nearly 45 years ago, these small positive-sense RNA viruses remain critically understudied. These studies provide fundamental new research on astrovirus pathogenesis and disruption of the gut epithelium by induction of epithelial-mesenchymal transition (EMT) following astrovirus infection. Here we characterize HAstV-induced EMT as an upregulation of SNAI1 and VIM with a down regulation of CDH1 and OCLN, loss of cell-cell junctions most notably at 18 hours post-infection (hpi), and loss of cellular polarity by 24 hpi. While active transforming growth factor- (TGF-) increases during HAstV infection, inhibition of TGF- signaling does not hinder EMT induction. However, HAstV-induced EMT does require active viral replication. These are among the first studies describing the induction of EMT by a non-oncogenic virus and provides an exciting opportunity to understand EMT induction independent of cancer. Our findings likely extend beyond astrovirus to other viruses and may shed light on novel ways pathogens can circumvent the barriers meant to protect against them. Crossing these barriers can lead to systemic and even fatal infections. Astroviruses can be especially problematic in immunocompromised individuals and infants where the virus has been associated with necrotizing enterocolitis, severe and persistent diarrhea, and even encephalitis and meningitis. Using our novel tools and models, we demonstrate that the FDA-approved broad-spectrum anti-infective drug nitazoxanide (NTZ) blocks astrovirus replication in vitro with a 50% effective concentration (EC50) of approximately 1.47μM. It can be administered up to 8 hours post- infection and is effective against multiple human astrovirus serotypes including clinical isolates. Most importantly, NTZ reduces viral shed in vivo, exhibiting its potential as a future clinical therapeutic. Overall, these studies will further our understanding of astrovirus pathogenesis leading to the development of therapeutic options for vulnerable populations. v TABLE OF CONTENTS CHAPTER 1. ASTROVIRUS VIROLOGY, PATHOGENESIS, AND DISEASE .....1 Virology ...........................................................................................................................1 Classification ................................................................................................................1 Genome ........................................................................................................................3 Virus Structure .............................................................................................................3 Replication Cycle .........................................................................................................5 Entry ........................................................................................................................ 5 Replication .............................................................................................................. 5 Assembly and Release ............................................................................................ 6 Pathogenesis .....................................................................................................................6 Molecular Mechanisms of Disease ..............................................................................6 Immune Response ........................................................................................................8 Disease .............................................................................................................................9 Clinical Features ..........................................................................................................9
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