Date of Award

8-2004

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T. Rouse

Committee Members

Robert Moore, Pamela Small, Albert T. Ichiki

Abstract

Herpetic Stromal Keratitis (HSK) is a leading cause of infectious blindness resulting from corneal infection with herpes simplex virus (HSV-1). Extensive corticosteroid therapy is required to achieve remission and sometimes corneal transplantation is the only means of restoring vision. Murine model research has revealed that the immunological process that clears infection conversely leads to corneal tissue damage. This immune-pathological reaction involves complex interactions of cellular and molecular events.

Current knowledge about human and murine HSK pathogenesis is summarized in Part I. Parts II, III and IV progresses this knowledge using knockout and transgenic mice. Results in Part II clarify mechanisms that operate shortly after corneal infection using a mouse with defective neutrophil migration. Impaired corneal neutrophil migration delayed corneal viral clearance causing heightened inflammation in the cornea. The cytokine IL-6, a component of this response, was shown to be capable of inducing VEGF, resulting in an increased angiogenic response and enhanced HSK lesions. These results provide novel insights into the link between viral infection, pro-inflammatory molecules, neutrophil migration, angiogenesis and HSK development. The role of HSV reactive and non-reactive CD8+ T cells in HSK pathogenesis is discussed in Parts III and IV. It has been demonstrated that CD4+ T cells, crucial to the development of HSK, do not require HSV antigen recognition to mediate HSK. Instead they are activated and recruited to the cornea by bystander mechanisms apparently through the action of pro-inflammatory molecules. Our recent results indicate that bystander mechanisms also facilitate corneal recruitment of non-HSV specific CD8+ T cells. However, HSV reactive CD8+ cells were not involved directly in corneal lesions but instead modulated lesion severity and protected mice from lethal HSV induced encephalitis. This latter effect appeared to be due to the ability of HSV specific CD8+ T cells to control viral replication in the peripheral nervous system and thereby prevent spread to both the brain and the cornea.

This dissertation presents research aimed at elucidating both molecular and cellular events in HSK pathogenesis. These results will serve as guidelines for future development of more efficient prophylactic and therapeutic strategies.

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