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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Intramural Research (Z01)
Project #
1Z01EY000240-17
Application #
6826527
Study Section
(LI)
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Hayashi, Kozaburo; Hooper, Laura C; Detrick, Barbara et al. (2009) HSV immune complex (HSV-IgG: IC) and HSV-DNA elicit the production of angiogenic factor VEGF and MMP-9. Arch Virol 154:219-26
Forooghian, Farzin; Macdonald, Ian M; Heckenlively, John R et al. (2008) The need for standardization of antiretinal antibody detection and measurement. Am J Ophthalmol 146:489-95
Hayashi, Kozaburo; Hooper, Laura C; Chin, Marian S et al. (2006) Herpes simplex virus 1 (HSV-1) DNA and immune complex (HSV-1-human IgG) elicit vigorous interleukin 6 release from infected corneal cells via Toll-like receptors. J Gen Virol 87:2161-9
Hooks, John J; Chin, Marian S; Srinivasan, Kumar et al. (2006) Human cytomegalovirus induced cyclooxygenase-2 in human retinal pigment epithelial cells augments viral replication through a prostaglandin pathway. Microbes Infect 8:2236-44
Djalilian, Ali R; Nagineni, Chandrasekharam N; Mahesh, Sankanaranayana P et al. (2006) Inhibition of inflammatory cytokine production in human corneal cells by dexamethasone, but not cyclosporin. Cornea 25:709-14
Chin, Marian S; Caruso, Rafael C; Detrick, Barbara et al. (2006) Autoantibodies to p75/LEDGF, a cell survival factor, found in patients with atypical retinal degeneration. J Autoimmun 27:17-27
Hooper, Laura C; Chin, Marian S; Detrick, Barbara et al. (2005) Retinal degeneration in experimental coronavirus retinopathy (ECOR) is associated with increased TNF-alpha, soluble TNFR2 and altered TNF-alpha signaling. J Neuroimmunol 166:65-74
Hooks, John J; Wang, Yun; Detrick, Barbara (2003) The critical role of IFN-gamma in experimental coronavirus retinopathy. Invest Ophthalmol Vis Sci 44:3402-8
Momma, Yuko; Nagineni, Chandrasekharam N; Chin, Marian S et al. (2003) Differential expression of chemokines by human retinal pigment epithelial cells infected with cytomegalovirus. Invest Ophthalmol Vis Sci 44:2026-33
Hooks, J J; Tso, M O; Detrick, B (2001) Retinopathies associated with antiretinal antibodies. Clin Diagn Lab Immunol 8:853-8

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