Our studies of various virologic and immunopathologic processes that occur when viruses and parasites replicate in the ocular microenvironment comprise four 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;and (4) herpesvirus infections of the eye. 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 evaluated very early cytokine and chemokine profiles as a measure of intensity of immune reactivity in coronavirus infected mice with a retinal degeneration susceptible and a retinal degeneration resistant background. These studies identified a distinct difference in the early immune response that is generated by the two mouse strains. These differences are noted in the production of IFN-gamma and the two chemokines triggered by IFN-gamma, CXCL9 and CXCL10. At day 2 and 3 PI, BALB/c mice have high levels of IFN-gamma, CXCL9 and CXCL10 in their sera. At the same time, significantly lower levels of these molecules are detected in sera from CD-1 mice. Moreover, real time PCR analysis of retinas identified that CXCL9 and CXCL10 gene expression is significantly greater in retinas from BABL/c mice in comparison to CD-1 mice. These studies are truly exciting and identify possible mechanisms that allow the BALB/c mouse to have a robust immune response that could trigger an autoimmune component. CXCL9 and CXCL10 are potent chemokines that interact with CXCR3 present on activated T cells and NK cells. They direct the migration and stimulate the adhesion of these cells. These T cells participate in immune reactivity against infected and self targets within the retina. Corneal herpes infection elicits a robust inflammatory response and eventually leads to a vision-threatening stromal keratitis as a sequela of frequent reactivation of latent virus. The aetiology of herpetic stromal keratitis (HSK) is thought to be an aberrant TH1 cytokine mediated immunopathology. HSK progresses in the absence of high levels of infectious HSV and is associated with angiogenesis and inflammatory mediators. In HSK patients, spread of HSV during reactivation is limited by neutralizing antibody. Therefore, components of HSV, such as HSV-DNA and neutralized HSV-IgG complexes (IC) may contribute to HSK by triggering mediators of angiogenesis and inflammation. An in vitro model system was employed to evaluate mechanisms by which viral components could induce inflammation and angiogenesis. We found that resident corneal cells (fibroblasts and epithelial) and macrophages are activated when treated with HSV-DNA or neutralized HSV-IC. These activated cells have augmented gene expression and protein production of VEGF and MMP-9. Moreover, these cells release proinflammatory cytkines that can further induce angiogenic factors. Further analysis revealed that the mechanisms involved in these processes include the Fc receptors and TLR interactions. Therefore, the continued presence of HSV-DNA and HSV-IgG IC within the ocular microenvironment may contribute to angiogenesis and inflammation observed in HSK, and cytokines and TLRs may be potential targets for intervention.
| 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 |
| Hayashi, Kozaburo; Hooper, Laura C; Hooks, John J (2008) Who (what) pays toll for the development of herpetic stromal keratitis (HSK). Semin Ophthalmol 23:229-34 |
| Detrick, Barbara; Lee, Maria Teresa; Chin, Marian S et al. (2008) Experimental coronavirus retinopathy (ECOR): retinal degeneration susceptible mice have an augmented interferon and chemokine (CXCL9, CXCL10) response early after virus infection. J Neuroimmunol 193:28-37 |
