The critical role of IFN-gamma in experimental coronavirus retinopathy.

Hooks, John J; Wang, Yun; Detrick, Barbara

PURPOSE Experimental coronavirus retinopathy (ECOR) is an animal model of progressive retinal disease that is first manifest as an acute retinal inflammation followed by chronic, immune-associated retinal degeneration in genetically susceptible, BALB/c mice. In retinal degeneration-resistant CD-1 mice, only the acute infection is seen. In the present study, interferon (IFN)-gamma production during ECOR was studied and its role evaluated in the clearance of infectious virus from the retina. METHODS BALB/c, CD-1, and IFN-gamma-deficient (IFN-gamma gko) mice were inoculated with the JHM strain of murine coronavirus by the intravitreal route. Mouse eyes were evaluated for infiltrating cells and major histocompatibility complex (MHC) expression by immunocytochemical staining. Isolated retinas were analyzed for IFN-gamma mRNA by RT-PCR, and sera were evaluated for IFN-gamma protein by ELISA assays. RESULTS Virus infection in BALB/c mice was associated with an increase in the incidence and levels of systemic IFN-gamma. Moreover, IFN-gamma mRNA was detected within the retinas of infected animals during the acute phase of the disease but was not detected in normal or mock-injected animals. IFN-gamma mRNA was detected at the time of T-cell infiltration, and earlier studies have shown that this is temporally related to granzyme B gene expression and the clearance of infectious virus from the retina. Retinal IFN-gamma mRNA was also associated with the upregulation of MHC class I and II molecules within the retina. When this infection occurred in IFN-gamma gko mice, the virus was unchecked, and the infection led to death. CONCLUSIONS These studies indicate that generation of IFN-gamma by cells infiltrating the retina is an essential part of an immune mechanism responsible for noncytolytic clearance of infectious virus from the retina.