Marian S. Chin

Experimental coronavirus retinopathy (ECOR): Retinal degeneration susceptible mice have an augmented interferon and chemokine (CXCL9, CXCL10) response early after virus infection

Abstract 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-α, IFN-β and IFN-γ act in concert as part of the innate immune response to the retinal infection. At day 2, high serum levels of IFN-γ, 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-γ 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.

Retinal degeneration in experimental coronavirus retinopathy (ECOR) is associated with increased TNF-α, soluble TNFR2 and altered TNF-α signaling

Abstract Experimental coronavirus retinopathy (ECOR) is a virally triggered model of retinal degeneration composed of both genetic and autoimmune components. Since TNF-α plays a role in immune-mediated processes we evaluated the levels of TNF-α/TNF-α receptors and the downstream signaling molecule nitric oxide (NO) during disease in both retinal degeneration susceptible BALB/c and degeneration resistant CD-1 mice. Following coronavirus injection, TNF-α mRNA was detected at higher levels within the retinas, and concentrations of TNF-α (p <0.005) and sTNFR1 (p <0.0005) proteins were increased within the sera of BALB/c but not CD-1 mice. While concentrations of sTNFR2 proteins were elevated in both BALB/c (p <0.00005) and CD-1 (p <0.005) mice compared to controls, concentrations were higher in BALB/c mice (p <0.0005). Gene expression of iNOS while initially high in BALB/c mice decreased during the acute phase of infection, while it increased in CD-1 mice. These trends are attributable to differences in monocyte TNFR2 release (p <0.0005) between the strains since sTNFR2 decreased (p <0.01) levels of NO production. These studies demonstrate that retinal degeneration following viral infection is associated with increased release of TNF-α/TNF receptors combined with a down-regulation of NO. Furthermore they suggest that these molecules are involved in alterations in immune response leading to autoimmune reactivity.

Identification of α-fodrin as an autoantigen in experimental coronavirus retinopathy (ECOR)

Abstract The coronavirus, mouse hepatitis virus (MHV), JHM strain 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 either the late phase or autoimmune reactivity. A mouse RPE/choroid DNA expression library was screened using sera from virus infected BALB/c mice. Two clones were identified, villin-2 protein and α-fodrin protein. α-Fodrin protein was used for further analysis and western blot reactivity was seen only in sera from virus infected BALB/c mice. CD4 T cells were shown to specifically react with MHV antigens and with α-fodrin protein. These studies clearly identified both antibody and CD4 T cell reactivities to α-fodrin in sera from virus infected, retinal degenerative susceptible BALB/c mice.