Ocular herpes virus infection is the most common infectious cause of blindness in the United States, but our understanding of the mechanisms that control the recurrence of this disease remains incomplete. The goal of this investigation is to elucidate the neuroimmunologic mechanisms which regulate neural latency and reactivation of herpes simplex virus type 1 (HSV-1) and which modulate corneal HSV-1 infection. It is hypothesized that primary corneal infection, latency, and reactivation of HSV-1 are, in part, regulated by neuroimmunoendocrinologic factors produced by neural cells and immunologically competent lymphocytes and that these cells and cytokines form the basis of a regulatory network.
The specific aims are: 1) To identify and isolate neuroendocrinologic mediators and cytokines in the cornea and neural ganglia; 2) To determine if alteration of the neuroimmunoendocrinologic network affects primary ocular HSV-1 infection and reactivation; 3) To determine the effects of various neuroendocrine mediators on lymphocytes sensitized to HSV-1 antigens; 4) To determine if HSV-1 antigen-specific lymphocytes produce neuropeptides and cytokines in response to antigen stimulation in vitro; 5) To determine if lymphocytes in the cornea and trigeminal ganglion produce neuropeptides and cytokines during HSV-1 infection; 6) To determine the population distribution of lymphocytes in the neural ganglia and cornea during primary and recurrent HSV-1 infection; 7) To determine the functions of the lymphocytes present in the neural and ocular tissue during primary and recurrent HSV-1 infection; 8) To determine the effect of immunization on the mononuclear cell infiltrate of the cornea and trigeminal ganglion during primary and recurrent HSV-1 infection; and 9) To determine the effect of lymphocyte depletion on the mononuclear cell infiltrate and infection of the cornea and trigeminal ganglion. Neural ganglia will be analyzed for the presence of adrenocorticotropin (ACTH), interleukin 1 (IL-1), interleukin 2 (IL-2), and gamma interferon (gamma IFN) by radioimmunoassay and Northern and Western gel-blot analysis. The capacity of neural ganglion cells and lymphocytes to produce a specific neuroendocrinologic mediator and cytokines will be determined using a reverse hemolytic plaque assay. The immunoregulatory effects of ACTH, IL-1, IL-2, and gamma IFN will be determined in vitro and in vivo. The effect of ACTH and cytokines on the antiviral activity of lymphocytes will be determined. The production of ACTH and the cytokines and the presence of mRNA for these mediators in cornea cells, trigeminal ganglion cells, and lymphocytes during HSV-1 infection will be determined by radioimmunoassay, Northern gel hybridization, and in situ hybridization. By employing a variety of methods it will be possible to develop a model for the interaction between the nervous system and the immune system during primary and recurrent ocular HSV-1 infection. The results of this study will permit the formulation of improved strategies for treating or possibly preventing recurrent herpetic disease in the human eye.
Showing the most recent 10 out of 18 publications
