ABSTRACT Viral infections of the eye can cause severe damage and impair vision. Cytomegalovirus (CMV) is a herpesvirus that infects the eye and persists for life, causing problems across the life-span of the host. Importantly, CMV causes the most common congenital (in utero) infection in the western world, with vision impairment being one common outcome. However, the mechanisms of disease are unknown and no animal models exist to begin dissecting pathophysiology or developing interventions. Moreover, like all herpesviruses, CMV establishes a persistent/latent infection and provocative evidence suggests that chronic CMV carriage contributes to age- related macular degeneration (AMD) and choroidal neovascularization. These outcomes may be related to the persistent activation of macrophages by CMV and/or the constant immune surveillance of virus in the eye. Again, mechanisms are undefined. Thus, there is a critical need for animal models to define mechanisms and test interventions. Our preliminary data suggest that MCMV infection of newborn BALB/c mice results in infection of the retina, large numbers of infiltrating hematopoietic cells, and markedly disrupted retinal development with focal distortions in the inner and outer nuclear layers. To our knowledge, this is the first description of a mouse model for symptomatic congenital CMV infection of the eye. The purpose of this RO3 proposal is to characterize this new model and to directly compare the immediate and long-term outcomes of infections that occur early and later in life. Aim 1 will define the progression of viral infection, including the kinetics of infection and the cells that are infected, as well as differences between infection of newborn mice and adult mice. Aim 2 will define the immune infiltration of the retina, determine the changes in tissue transcriptional profile induced by infection, and test whether a viral chemokine is critical for initiating recruitment of hematopoietic cells and pathology. Aim 3 will determine the long-term effects of chronic MCMV carriage. These studies will provide a critical foundation for future work testing interventions and dissecting the mechanisms of CMV-induced disease in the presence of a functional, developing, immune system, and the long-term outcomes of such early-life infections.

PROJECT NARRATIVE Cytomegalovirus (CMV) is a herpesvirus that causes ocular disease across the life-span. CMV causes a common congenital (in utero) infection with vision impairment being a frequent outcome, while life-long persistence of CMV has been linked with age-related macular degeneration (AMD). This proposal will investigate a novel model that recapitulates retinal damage after congenital CMV infection and define the immediate and long-term impact of such early-life ocular CMV infections.