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The Impact of Sex and Species of Cells in Herpes Simplex Virus Infection

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The Impact of Sex and Species of Cells in Herpes Simplex Virus Infection The impact of sex and species of cells in herpes simplex virus infection Yeu-Yang Tseng April 2019 A thesis submitted for the degree of Doctor of Philosophy of The Australian National University © Copyright by Yeu-Yang Tseng 2019 All Rights Reserved ii Declaration The work in this thesis was performed at the Australian National University. To the best of my knowledge, this thesis contains no material, which has been accepted for the award of any other degree or diploma in any university. It does not contain material previously published or written by another person, except where reference is made in the text. Yeu-Yang Tseng April 2019 iii iv Acknowledgment I still remember the first day I arrived in Canberra carrying a feminine suitcase (thanks my dear mom) alone in a bloody cold winter (2015). After wolfed down tasteless instant noodles, my supervisor Professor David Tscharke rescued me from my pity and uninhabited room by taking me to purchase basic life needs. This is how David is important for me during my PhD journey. Without his invaluable guidance and sometimes crazy ideas, this project would never have been accomplished. His door is always open to his students for scientific discussion. It is hard to express how grateful I am for having him as my PhD supervisor. I am really glad to have him as my supervisor as well as a friend. My deep appreciation also goes to all the members of my supervisory panel, Dr. Si Ming Man, Dr. Gaétan Burgio and Dr. Michael Frese for their suggestion and support. They are not just like distant relatives turning up once a year at a family event during Christmas holidays. We discussed how to improve this project and shared ideas quite often. I would like to especially thank Dr. Si Ming Man for putting every effort into modifying my two manuscripts. I need to thank the other fantastic collaborator, Dr. Zhi- Ping Feng who transferred my wet-lab life into a semi-dry one. With her insight and expertise, we would be able to analyse our big data accurately and efficiently. I also thank all the members of the Tscharke lab: Stewart Smith, Inge Flesch, Tiffany Russell, Thilaga Velusamy, Anjali Gowripalan, Matthew Witney, Navneet Singh and Sherin. Their friendships and having morning tea together are the base for me to survive in this process. Warm encouragements from Taiwan are always the cure for my homesickness. Dr. Wei-Li Hsu and Dr. Jui-Hung Shien are as supportive as they used to be since my college time. My sincere thanks also extend to Messi Chou and Strawberry Liao for talking nonsense with me and occupying my cherished times. It is my pleasure to meet Eden Chen in the toughest time in my life and I am profoundly grateful for you being understanding, supportive and always there. Thank you my buddies in Canberra, George Yu and Aaron Sung, for doing grocery shopping every week with and fooling around the Australia together. Of course, I did not forget my dad and my brother who lured me with irresistibly sponsored (i.e. free) flight tickets to coming home and picked me up all the time at the airport in Taiwan. v vi Abstract Herpes simplex virus type I (HSV-1) is a large, enveloped DNA virus which belongs to the Herpesviridae family. HSV-1 is a highly infectious human pathogen that contacts mucosal surfaces to initiate infection and causes a range of diseases from mild cold sores to keratitis and encephalitis. A growing number of studies point to a sex difference in the prevalence and severity of viral infections. However, the role for sex in herpes infection is unclear due to the complexity of factors involving in the manifestation of HSV diseases. Furthermore, many primary infections are asymptomatic, contributing to the difficulty of studying HSV infections in humans. The neurotropic properties of HSV make it harder to reach information from infected humans for investigating the immune mechanisms controlling reactivation of latent infection within sensory ganglia or central nervous system. Therefore, mouse models have been used extensively to understand multiple aspects of HSV pathogenesis. However, the molecular basis underpinning cross-species differences between humans and mice in response to HSV- 1 infection is unknown. In this thesis, we asked whether these two factors, sex and species, may influence HSV-1 replication. Much progress towards these goals has been made using reductionist approaches such as in vitro cell cultures and in many situations this is the only way that cell-intrinsic mechanisms can be dissected. We demonstrated that HSV-1 can adapt to specific sex and generate different mutations due to selective pressure derived from different sexes. Next, profiling of male and female transcriptomic programs revealed that the cytosolic sensing pathway is induced to a greater degree in female primary mouse skin cells (female cells), correlating with higher yields of infectious virions in male counterparts (male cells). In addition, female cells distinctively reactivated Xist, a critical component of X-inactivation, to silence the expression of the transcriptional repressor on the X chromosome, which thereby maintained higher innate immune responses and further explains the different growth phenotypes in HSV-1 replication between the two sexes. Collectively, we propose a model in which HSV-1 triggers a sex-specific regulation of antiviral response in the cytosolic sensing signalling via the control of Xist. During investigation of the sex difference, we coincidently found that viperin, an interferon-stimulated gene (ISG), is upregulated in mouse but not in all tested human cells, which is related to previous findings in the field and encouraged us to comprehensively study human-mouse differences in HSV-1 infection. We show that the growth kinetics of HSV-1 differed substantially in human and mouse cells. A vii computational pipeline was developed to analyse the cross-species RNA sequencing data, revealing over 60% of differentially regulated pathways between these two hosts in cell cultures. Strikingly, mouse cells upregulated more genes in the antiviral pathway driven by ISGs. To identify the key factor that influences the cross-species difference, we identified that Janus kinase 1 (Jak1) is essential for contributing to the human-mouse difference in HSV-1 replication. Lastly, we utilized virus mutants to show that HSV-1 vhs plays an important role to regulate JAK1 expression and therefore activation between human and mouse cells. In summary, this thesis has expanded our understanding on basic differences of cell cultures that sex and species can affect scientific interpretations in virus infection. Furthermore, the results presented in this study provide rich resources to translate data between the two sexes or mouse experiments into the human disease. viii Table of contents Declaration ........................................................................................................................................ iii Acknowledgment ............................................................................................................................. v Abstract ............................................................................................................................................. vii Table of contents ............................................................................................................................. ix List of figures.................................................................................................................................. xiv List of tables ................................................................................................................................. xviii Abbreviation ................................................................................................................................... xix Chapter 1. Introduction .................................................................................................................. 1 1.1 Herpes simplex virus .......................................................................................................... 3 1.1.1 HSV-1 virion and genome ........................................................................................ 3 1.1.2 HSV-1 epidemiology and diseases ........................................................................ 6 1.1.3 HSV-1 life cycle ............................................................................................................ 8 1.1.4 HSV-1 gene expression .............................................................................................. 9 1.2 Recognition of HSV-1 in host cells .............................................................................. 12 1.2.1 Toll-like receptors (TLRs) ..................................................................................... 13 1.2.2 Cytosolic DNA sensors ............................................................................................ 15 1.2.3 Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) ................ 16 1.3 Downstream signalling pathways after sensing HSV-1 ...................................... 17 1.3.1 Canonical IFN signalling pathway ..................................................................... 20 1.3.2 IFN-independent mechanisms .............................................................................. 21 1.4 Regulation of viperin and its role in innate antiviral responses ..................... 21 1.5 Herpesviral proteins that evade DNA sensing and the IFN pathway
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