The impact of sex and species of cells in herpes simplex virus infection
Creators: name: Tseng, Yeu-Yang
Publisher: name: The Australian National University
Year: 2019

description: 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 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.