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Extremes in Timing of Mycobacterium Tuberculosis Infection: Implications For Extremes in Timing of Mycobacterium tuberculosis Infection: Implications for Managing Human Susceptibility to Tuberculosis DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Russell Ault Biomedical Sciences Graduate Program The Ohio State University 2020 Dissertation Committee Joanne Turner, PhD, Advisor Amy Lovett-Racke, PhD, Co-advisor Larry Schlesinger, MD Jeffrey Parvin, MD, PhD Christopher Walker, PhD Copyrighted by Russell Ault 2020 2 Abstract Tuberculosis (TB) is the leading killer due to a single infectious disease worldwide. It is caused by the bacterium Mycobacterium tuberculosis (M.tb) and is spread via the airborne route. Only a small proportion of people who become infected with M.tb develop disease and are capable of transmitting the bacteria to others. The capability to identify M.tb-infected people who will actually go on to develop disease is critical. With current methods, treating everyone who has ever been exposed to M.tb to prevent disease likely will cause more harm than benefit due to the potential adverse side effects of treatment. There is a crucial need to target preventive treatment to those who most need it. With the aging of the global population, the case rate and deaths due to TB are highest in the elderly population. While general immunosenescence associated with old age is thought to contribute to the susceptibility of the elderly to develop active TB disease, very few studies of immune function in elderly individuals with M.tb infection or disease have been performed. Based on an analysis of T cell function and monocyte phenotypes in the blood, we observed no strong evidence that the peripheral blood immune response specific to M.tb in elderly individuals is altered relative to younger adults. This is consistent with the available strong epidemiologic data based on longitudinal birth ii cohorts that TB disease incidence declines throughout the lifespan well into old age. Our work highlights the need for research identifying biomarkers that allow better assessment of an elderly person’s risk of developing TB disease after infection. It is critically important to know whether an elderly person has been infected recently, with a high risk of disease progression, or earlier in their life, with the lowest risk of progression during their entire lifetime. Recent M.tb infection is the strongest clinical risk factor for progression to TB disease in immunocompetent individuals, who comprise the majority of TB disease cases. However, time since M.tb infection is challenging to determine in routine clinical practice. To define a biomarker for recent TB exposure, we determined whether gene expression patterns in blood RNA correlated with time since M.tb infection or exposure. First, we found RNA signatures that accurately discriminated early and late time periods after experimental infection in mice and cynomolgus macaques. Next, we found a blood RNA signature that identified recently exposed individuals in two independent human cohorts. However, for M.tb infected adolescents and adult household contacts of TB cases, our RNA signature of recent infection was unable to provide prognostic information for TB disease progression, possibly because of its brief duration. Our work supports the need for future longitudinal studies of recent TB contacts to identify biomarkers of recent infection that have sufficient duration to provide prognostic information of TB disease risk in individuals and to help map recent transmission in communities. Such a biomarker would be useful in all populations, including the elderly. iii Dedication To the patients I have met who have suffered from tuberculosis. To those who will yet suffer from this disease. I hope this work will help you in some small part. To my devoted wife, Rachel, who has provided me immense support. Thank you. iv Acknowledgments I would like to acknowledge my advisor, Dr. Joanne Turner. Thank you for accepting me into your research team and for your unparalleled support these past several years. Thank you for training me to be a scientist, with all the sacrifice and effort this has taken from you. I also thank you for the opportunity to come to Texas and to pursue my own ideas as reflected in the work of this dissertation. I would like to acknowledge past and present members of the Turner laboratory, all of whom have contributed to the work described in this dissertation: Joshua Cyktor, Bridget Carruthers, Elisha Koivisto, Jenna Nagy, Jacob Horvath, Cynthia Canan, Varun Dwivedi, Colwyn Headley, Tucker Piergallini, Shalini Gautam and Julia Scordo. You have been wonderful to work with, and I greatly appreciate your help these past few years. I would like to thank Dr. Jordi B. Torrelles and past and present lab members Michael Duncan, Juan Moliva, Holden Kelley, Andreu Vilanova, Anna Guardia, Kizil Yusoof, Anwari Akhter, Paula Tamayo and Angelica Olmo-Fontanez. My association with you and our discussions have been invaluable. v I acknowledge the BSL3 programs and former and present staff at both The Ohio State University and Texas Biomedical Research Institute, including Lena Lynch, Austin Hossfeld, Journey Cole, Ariana Duffey, Heather Guenther and Beata Clapp. Thank you to Alison Whigham and the rest of the vivarium staff at Texas Biomed. I also especially thank Dr. Shannan Hall-Ursone for aid in mouse training and veterinary assistance. I thank the analytical cytometry shared resource at The Ohio State University and acknowledge the efforts of the Baylor Institute for Immunology Research Genomics core for assistance with sample preparation and microarray processing. I thank the molecular core facility at Texas Biomed, and especially Clinton Christensen and Jeremy Glenn. I thank Frederic Chevalier, Jack Kent, Sandra Smith and Richard Polich for helping me set up and for support with computing resources at Texas Biomed. I thank the Data Science Club at OSU for inspiration in the beginning of my research. I greatly thank my PhD dissertation committee members, Amy Lovett-Racke (co- advisor), PhD, Larry Schlesinger, MD, Jeffrey Parvin, MD-PhD, and Christopher Walker, PhD, for providing me guidance and support throughout my PhD. Thank you to all of our collaborators on this work: Karin Miller, MD, Kokila Nagendran, MD, Indu Chalana, MD, Xueliang Pan, PhD, Shu-Hua Wang, MD, MPH&TM, Alexander Hare, Esko Kautto, Quais Hassan, Asuncion Mejias, MD-PhD, Melanie Carless, PhD and Blanca Restrepo, PhD. I would like to thank past and present members of the OSU Department of Microbial Infection and Immunity and former members of the vi former OSU Center for Microbial Interface Biology, as well as scientists and staff at Texas Biomed for feedback, advice, guidance and support in my path to become a scientist. I likewise thank the Medical Scientist Training Program at OSU, as well as the Medical Scientist Training Program at UT-Health San Antonio, who have graciously allowed me to join in on programmatic events and training opportunities during my PhD. I especially thank our human study participants as well as clinic staff at The Ohio State University Wexner Medical Center and Columbus Public Health for assistance in subject recruitment. Finally, I thank my wife, Rachel, who has supported me through the ups and downs of PhD training and who has always believed in me. The work described in this dissertation is contained in two manuscripts, both under Creative Commons BY-4.0 International licenses (https://creativecommons.org/licenses/by/4.0/), allowing free re-use and modification under terms of providing attribution and not restricting others’ use of the license. Substantial text is taken verbatim, with some additions. These manuscripts are (1, 2): R. Ault, V. Dwivedi, E. Koivisto, J. Nagy, K. Miller, K. Nagendran, I. Chalana, X. Pan, S.-H. Wang, J. Turner, Altered monocyte phenotypes but not impaired peripheral T cell immunity may explain susceptibility of the elderly to develop tuberculosis, Exp. Gerontol. 111, 35–44 (2018). R. C. Ault, C. A. Headley, A. E. Hare, B. J. Carruthers, A. Mejias, J. Turner, Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans, bioRxiv , 830794 (2019). vii Vita June 2008…………………………………………………Diploma, Fairfield High School May 2014………..…………………………B.S. Molecular Biophysics and Biochemistry, Yale University 2014-2016….………………………………………….Medical Student, Medical Scientist Training Program, The Ohio State University 2016-2020…………………………………...…………………Graduate Research Fellow, Biomedical Sciences Graduate Program, The Ohio State University Publications R. Ault, V. Dwivedi, E. Koivisto, J. Nagy, K. Miller, K. Nagendran, I. Chalana, X. Pan, S.-H. Wang, J. Turner, Altered monocyte phenotypes but not impaired peripheral T cell immunity may explain susceptibility of the elderly to develop tuberculosis, Exp. Gerontol. 111, 35–44 (2018). J. I. Moliva, M. A. Duncan, A. Olmo-Fontánez, A. Akhter, E. Arnett, J. M. Scordo, R. Ault, S. J. Sasindran, A. K. Azad, M. J. Montoya, N. Reinhold-Larsson, M. V. S. Rajaram, R. E. Merrit, W. P. Lafuse, L. Zhang, S.-H. Wang, G. Beamer, Y. Wang, K. Proud, D. J. Maselli, J. Peters, S. T. Weintraub, J. Turner, L. S. Schlesinger, J. B. Torrelles, The Lung Mucosa Environment in the Elderly Increases Host Susceptibility to Mycobacterium tuberculosis Infection, J. Infect. Dis. 220, 514–523 (2019). viii P. McGillivray, R. Ault, M. Pawashe, R. Kitchen, S. Balasubramanian, M. Gerstein, A comprehensive
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