| Coronaviruses have been shown to cause eye infection in cats (Doherty, 1971; Krebiel et al., 1974; August, 1984), pigs (Andries et al., 1980), and rats (Lai et al., 1976), as well as retinal degeneration in rat (Hogan et al., 1983) and mouse (Bailey et al., 1949) models of neurodegenerative disease. Previous studies have shown the development of retinopathy, a noninflammatory degenerative disease of the retina, in BALB/c, but not in CD-1, mice following intravitreal injection of the murine coronavirus, mouse hepatitis virus (MHV) (Wang et. al. 1996). In addition antiretinal antibodies have been detected in these BALB/c mice (Hooks et al., 1993). These results indicate that there is both a genetic as well as an immunologic component to the development of retinopathy. Knowledge of the factors involved in disease progression may lead to new therapies for retinal diseases.; In an effort to determine factors that may be important to the development of retinopathy following coronavirus infection we looked for differences in the responses of susceptible (BALB/c) versus non-susceptible (CD-1) mice. Two factors that were identified were TNF-α and its receptor TNFR2 (p75, p80). Levels of TNF-α mRNA as well as protein were higher in susceptible mice early in infection (day 4). Concentrations of soluble TNFR2 were significantly increased (p < .0005) in retinopathy-susceptible mice compared to nonsusceptible mice at this same timepoint. Increased levels of TNFα and soluble TNFR2 were attributed to differences in leukocyte functioning between susceptible and nonsusceptible animals. The concentrations of TNF-α were not important for control of MHV as TNF-α had no direct effect on MHV replication or on animal survival using TNF-α knockout (KO) mice. Lymphotoxin (TNF-β) and TNFR2 on the other hand, were shown to be critical for animal survival using KO mice. At the molecular level, susceptible BALB/c mice showed decreases in the level of mRNA for caspase 8 and inducible nitric oxide synthatase (iNOS) indicating that function via TNF-α receptors had been altered. Collectively, these results demonstrate the importance of TNF family members in viral clearance as well as the development of degenerative disease following viral clearance. |
