Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Microbiology and Immunology
Supervisor
Troyer, Ryan M.
Abstract
Herpesviruses are among the most ubiquitous vertebrate viruses and are defined both by their lifelong latent infections of the host cell, and their masterful manipulation of cellular processes including protein degradation, intracellular signalling, and gene expression. Herpesviruses have evolved alongside their hosts and control host cell functions through a varied array of mechanisms, often through protein-protein interactions. Herpesviruses are transmitted predominantly through infected bodily fluids including saliva and typically exist asymptomatically within the host. However, lytic replication triggered by chemical or physiological factors may result in a diverse set of pathologies. The lymphotropic herpesvirus sub-family, gammaherpesviruses (GHV), also contribute to a range of pathologies in humans and animals including fatal cancers. To improve our understanding of both the prevalence of GHVs and their manipulation of host cellular processes, we investigated the epidemiological characteristics of a novel feline GHV, called Felis catus gammaherpesvirus 1 (FcaGHV1), as well as the function and mechanism of two novel FcaGHV1 proteins through a range of molecular biology methods. We found that FcaGHV1 glycoprotein B (gB) DNA was shed in domestic feline saliva from cats in southwest Ontario with a frequency similar to published literature. We also confirmed conservation of FcaGHV1 gB in southwest Ontario to other FcaGHV1 isolates worldwide, and attempted isolation of FcaGHV1 in cell culture. Furthermore, we elucidated the function and mechanism of the viral E3 ligase F10, which downregulates host surface MHC-I to aid viral survival by immune evasion through an endoplasmic reticulum-associated degradation-dependent and proteasome-dependent mechanism. Finally, we characterized the putative mechanism of F20, a novel FcaGHV1 ORF categorized as an “ORFan” due to its lack of homology to any published genes or protein. F20 triggers widespread host gene downregulation, potentially through manipulation of host p38 and JNK MAPK signalling via virus-host protein interactions. Our results warrant further investigation of FcaGHV1 epidemiology and the mechanisms of its repertoire of novel ORFs and proteins. Our work contributes to the growing knowledge pool of GHV prevalence and shedding, as well as the mechanisms by which GHVs manipulate host cell processes to aid viral survival and replication.
Summary for Lay Audience
Herpesviruses infect many vertebrate species including humans, and hosts remain infected for their entire life span. Herpes often spreads through bodily fluids like saliva, and infections are typically asymptomatic, but disease may occur in the case of immunocompromised hosts, or under other physiological or environmental conditions including stress, illness, sunlight, and fatigue. Diseases include relatively minor conditions like cold sores or chickenpox, but also include fatal cancers, especially in the case of a sub-family of herpesviruses called gammaherpesviruses. Life-long herpes infections are predominantly due to the large herpesvirus genomes that encode many different viral proteins that can control host cell processes. For example, many herpesviruses have evolved ways to hide the infected cell from the immune system by removing host proteins from the surface of the cell that are normally responsible for initiation of an immune response. This thesis concerns a novel gammaherpesvirus in domestic cats called Felis catus gammaherpesvirus 1 (FcaGHV1). We investigated how frequently FcaGHV1 infects cats and how the virus is shed from infected feline saliva. We also studied two proteins encoded by the virus, including F10, which helps the virus hide from the host immune system, and F20, which may interrupt intracellular signaling to prevent host gene expression. We found that FcaGHV1 DNA was shed in cat saliva at a frequency similar to previously published studies on FcaGHV1 prevalence. We also discovered that the protein F10 prevents the host cell from expressing a protein key to the initiation of an immune response, and that the protein F20 likely interrupts cellular communication by binding key host proteins. This research contributes to the growing pool of knowledge concerning how herpesviruses spread and how they remain in their hosts for the rest of their lives by manipulation of host cell processes. This work may help not only to improve the health and well-being of domestic cats, but also inform future efforts to develop medicines for disease caused by herpesvirus infections in other animals and humans.
Recommended Citation
Hill, Malcolm Alistair Munro, "Investigation of Novel Herpesvirus Felis catus Gammaherpesvirus 1: Salivary Shedding, Immune Evasion, and Manipulation of Cellular Gene Expression" (2025). Electronic Thesis and Dissertation Repository. 10685.
https://ir.lib.uwo.ca/etd/10685
Creative Commons License
This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 License.
