Mouse hepatitis virus induces a biphasic disease in BALB/c mice that consists of an acute retinitis followed by progression to a chronic retinal degeneration with autoimmune reactivity. Retinal degeneration resistant CD-1 mice do not develop the late phase. What host factors contribute to the distinct responses to the virus are unknown. Herein, we show that IFN-alpha, IFN-beta and IFN-gamma act in concert as part of the innate immune response to the retinal infection. At day 2, high serum levels of IFN-gamma, CXCL9 and CXCL10, were detected in BALB/c mice. Moreover, elevated levels of CXCL9 and CXCL10 gene expression were detected in retinal tissue. Although IFN-gamma and the chemokines were detected in CD-1 mice, they were at significantly lower levels compared to BALB/c mice. These augmented innate responses observed correlated with the development of autoimmune reactivity and retinal degeneration and thus may contribute to the pathogenic processes.