Herpes Virus Entry Mediator (HVEM) and Ocular Herpes: More Than Meets the Eye

Rebecca Giovanna Edwards
2016 unpublished
Herpes Virus Entry Mediator (HVEM) and Ocular Herpes: More Than Meets the Eye Rebecca G. Edwards Herpes stromal keratitis (HSK) is a potentially blinding inflammatory condition initiated by corneal infection with herpes simplex virus (HSV). As its name suggests, the host receptor herpes virus entry mediator (HVEM) facilitates HSV entry through interactions with a viral envelope glycoprotein. HVEM also bridges several signaling networks, binding ligands from both TNF-and Ig-superfamilies with
more » ... erse, and often opposing, outcomes. While it has long been established as an entry receptor for HSV-1, HVEM has only recently emerged as a host factor important for pathogenesis of ocular herpetic disease. HVEM KO mice are protected from severe systemic disease, including neurologic morbidity, viral spread, and epithelial lesion development. To investigate the contribution entry makes to this process, I infected mice with a mutant HVEM entry-null virus; to my surprise, I found that HVEM-mediated pathogenesis does not require the gD-HVEM interaction, indicating its effects are separable from viral entry. In addition, adoptive transfer experiments show that susceptibility to disease coincides with the presence of HVEM on radiation-resistant cell type(s). In contrast to previous reports, the majority of HVEM in the cornea is found on monocyte-lineage cells rather than on corneal epithelial cells, suggesting HVEM on resident macrophages may account for pathogenesis in our model. Characterization of corneal-specific disease revealed HVEM increases inflammatory cytokine expression and stromal immune cell infiltrates, and exacerbates corneal nerve damage. Together, these findings demonstrate HVEM has a central and multifaceted role in the immunopathogenesis of HSK, impacting not only viral replication and spread, but also chronic I would like to thank the members of my thesis committee for their invaluable guidance in the development and refinement of my experiments, and for their contributions to my education as a scientist. Dr. Bill Muller has been generous with his time both when it came to discussions of my project, but also with allowing me to shadow him on clinical duties, which kept the ultimate goals of my training in the forefront of my mind. In addition to providing much-needed expertise in the field of corneal biology and sharing critical reagents, such as mice, with me, Dr. Robert Lavker also fostered my interest in ophthalmology, helping me network with eminent scientists and physician-scientists both at our home institution as well as at a national conference. I am extremely grateful to Dr. Stephen Miller and members of his laboratory, especially Dr. Igal Ifergan, without whom many of the experiments in my thesis would not be possible. Dr. Miller and Dr. Ifergan were extremely patient with me, and spent a great deal of time and energy helping me with both flow cytometry experiments and nanoparticle therapy experiments, the results of which form some of the most interesting findings in all of my research.
doi:10.21985/n2v68c fatcat:bcqr3hbasjexpgbd46jnjcaabq