Studies were initiated to explore the physiologic and evolutionary significance of keratocyte apoptosis occurring in response to epithelial injury. Corneal epithelial scrape and refractive surgery were probably not the pressures that led to the evolution of this response. We hypothesized that perhaps this could represent some form of early response to viral infection of the corneal epithelium, a cellular "fire break" to retard posterior extension of viruses such as herpes simplex virus or smallpox virus that require living cells to spread. These viruses typically infect the corneal epithelium, but may also infect the underlying keratocytes and endothelial cells and extend to other cells of the eye and central nervous system. Studies we performed6 provided evidence to support this hypothesis. When rabbits were infected with herpes simplex virus, without initial scarification, thymidine-medicated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) assay and electron microscopic analysis revealed keratocytes beneath areas of epithelial infection undergoing apoptosis. Stat-1 null mice have a defective keratocyte apoptosis response to epithelial scrape injury.7 When Stat-1 null mice were infected via corneal surface inoculation with herpes simplex virus, they had overwhelming corneal infection that often led to central nervous system infection and death (James Hill, PhD, et al, unpublished data, 1999). It is difficult to verify whether diminished keratocyte apoptosis was the sole source of this fulminate infection since Stat-1 null mice also have defects in interferon production.