Virus Infections In The Eye

National Eye Institute

Investigators

Linked publications & trials

Abstract

Our studies of various virologic and immunopathologic processes that occur when viruses and parasites replicate in the ocular microenvironment comprise five areas: (1) virus induced retinal degenerative processes; (2) the possible roles of viruses in human diseases; (3) molecular diagnosis and pathogenesis of cytomegalovirus (CMV) infections in man; (4) herpesvirus infections of the eye and (5) Toxoplasma gondii infections of the retina. We have established a model system for studying retinal degenerative diseases, experimental coronavirus retinopathy (ECOR). The virus is capable of inducing an acute infection in the presence of mild retinal vascular inflammation. Initial retinal damage is followed by clearance of infectious virus and progressive retinal degeneration. This is the first retinal model to demonstrate a virus induced degeneration, viral persistence, a genetic predisposition to virus induced tissue damage and a virus triggered autoimmune response. Our goal is to determine the pathophysiological mechanisms and to identify genes involved in the retinal degenerative disease. During the past year we have made the following key findings. Since TNF-a plays a crucial role in immune-mediated processes we evaluated the levels of TNF-a/TNF-a receptors and the downstream signaling molecule nitric oxide (NO) during the course of disease in both retinal degeneration susceptible BALB/c and degeneration resistant CD-1 mice. Following intravitreal injection with the coronavirus, mouse hepatitis virus (MHV), TNF-a mRNA was detected at higher levels within the retinas, and concentrations of TNF-a and sTNFR1 proteins were significantly increased, p<0.005 and p< 0.0005 respectively, within the serum 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 significantly 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 significantly decreased (p < 0.01) levels of NO production. These studies demonstrate that retinal degeneration following viral infection is associated with increased release of TNF-a and TNF receptors combined with a down-regulation of NO. Furthermore they suggest that these molecules are involved in alterations in immune response leading to the autoimmune reactivity seen in retinal degeneration susceptible mice. Based on the animal model system, we have also initiated studies to evaluate human retinal degenerative diseases. Autoantibodies were detected in patients with retinopathy of unknown origin by immunocytochemical staining and western blot analysis. Using patient sera, a rat retina cDNA expression library was screened and positive clones were identified. One of the clones demonstrated 88% identity to lens epithelium-derived growth factor / transcription coactivators p52 and p75/DSF70. These data suggest that antibodies directed against p75/p52 identified in this patient may contribute to her retinopathy. Human CMV is a herpesvirus that is a major cause of blindness in children born with congenital infections and in immunocompromised individuals. It is difficult to study CMV latency in man. Therefore cell culture models of CMV replication and latency may provide insight into a rationale for alternative treatment modalities. Chemokines regulate leukocyte trafficking and may be important in inflammatory cell recruitment into the retina. HCMV infection in HRPE cells resulted in modulation of three important chemokines, MCP-1, MCP-3 and IL-8. The levels of MCP-1 and MCP-3 mRNA and protein in HCMV infected HRPE were reduced in comparison to uninfected HRPE. In contrast, HCMV infection enhanced IL-8 mRNA annd protein levels. Because chemokines facilitate the migration and activation of leukocytes to the sites of inflammation, the modulation of chemokines production by the virus suggests a possible mechanism in immune evasion of immunopathogenesis for HCMV in retinitis and immune recovery uveitis.