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. We undertook the characterization of ECOR to examine the potential contribution of IFN-gamma in the clearance of infectious virus in the retina. We found that IFN-gamma was produced during ECOR, and IFN-gamma gene expression was detected within the retina. The presence of IFN-gamma was asssociated with the activation of host immune response to MHV infection, and the absence of IFN-gamma in IFN-gamma deficient mice was associated with a dramatic increase in viral encephalitis and death. 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. 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 and 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.
Showing the most recent 10 out of 16 publications
