There are approximately 50,000 cases of new or recurrent ocular HSV disease per year in the U.S., with stromal scarring of the cornea leading to reduced visual acuity in about 6,000 patients per year. Acute and recurrent herpes simplex keratitis are leading indications for corneal transplantation in this country. Ultraviolet light (UV) exposure, fever, hyperthermia, hypothermia, dental trauma and surgical manipulation of the trigeminal ganglion are stimuli associated with reactivation of HSV-1. The sequence of HSV gene activation during productive infection is well known, but the mechanism by which reactivation stimuli, including UV light, stimulate latent virus to replicate is unknown. Studies by the principal investigator have shed new light on this mysterious process, implicating the inflammatory cytokine interleukin-6 (IL-6) and its associated cellular transcription factor STAT3 in the pathogenesis of ocular HSV reactivation. New supporting data presented in this application demonstrates that ocular UV exposure induces IL-6 production in explanted corneas. By contrast, the same UV stimulus induces and activates the transcription factor STAT3 in the trigeminal ganglion, the site of the latent viral infection, where this factor is hypothesized to initiate HSV-1 gene transcription.
This specific aims of this proposal are to: 1)Investigate the role of IL-6 in the murine keratitis model by: a) directly injecting IL-6 into the conjunctiva of latently infected mice and b) studying the ability of IL-6 knockout mice to reactivate HSV-1. 2)Explore the hypothesized IL-6STAT mechanism of induced HSV ocular reactivation. Based on supporting data, studies are proposed: a) to detect activated, phosporylated STAT transcription factors and b) determine whether these factors specifically bind important HSV-1 genes. 3)Directly investigate the hypothesis that IL-6 drives HSV-1 gene transcription. A collaborative effort is outlined to study this using HSV-1 transient expression and/or reporter construct assays. Novel and specific viral mutants will be constructed based on the results of HSV-DNA binding and transient expression assays.
| Kriesel, John D; Jones, Brandt B; Dahms, Kimberly M et al. (2004) STAT1 binds to the herpes simplex virus type 1 latency-associated transcript promoter. J Neurovirol 10:12-20 |
| Kriesel, J D; Jones, B B; Hwang, I P et al. (2001) Signal transducers and activators of transcription (Stat) are detectable in mouse trigeminal ganglion neurons. J Interferon Cytokine Res 21:445-50 |
