Receptor Usage and Regulation of the Immune Response in HSV Infection

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Project Description: Herpes simplex virus type I (HSV-1) infection is often asymptomatic or may produce recurrent lesions in and around the mouth, commonly called “cold sores.” Ocular herpetic disease, typically caused by HSV-1 either through primary infection or reactivation from the trigeminal ganglia (TG), can have serious sequelae, including permanent corneal scarring and blindness. Herpes stromal keratitis (HSK) is one of the most common causes of infectious blindness in the developed world, and worldwide produces over 40,000 new cases of severe vision impairment or blindness each year. Interestingly, the majority of HSK tissue damage is thought to be immune-mediated rather than resulting from direct lytic effects of the virus. Even after the virus has successfully been cleared, high levels of inflammatory cytokines and chemokines, immune cell infiltrates, and neovascularization persist. How HSV-1 infection of the eye leads to this chronic inflammatory syndrome is not well understood. By studying cellular factors that influence the host immune response, we will delineate the cascade of events that begin with a viral infection and end with chronic inflammation and vision loss. This proposal represents a continuation of our studies examining cellular factors that are important for HSK using a murine model. The studies proposed here will address the immunomodulatory functions of PILRA and HVEM in Herpes Simplex Virus (HSV) Keratitis. By investigating how PILRA and HVEM contributes to HSK, we will better understand the viral-host interactions inflammatory syndrome that persists in the absence of replicating virus, providing a basis for therapeutic interventions for HSK.