Doctoral Dissertations

Date of Award

8-2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T. Rouse

Committee Members

Stephen J. Kennel, Michael F. McEntee, Seung J. Baek

Abstract

Herpes simplex virus (HSV) infection of the cornea leads to a blinding immuno-inflammatory condition of the eye also called stromal keratitis (SK). SK immunopathology is characterized by the infiltration of CD4+ T cells of Th1 phenotype as well as the development of new blood vessels into the normally avascular cornea. Studies in mouse models of SK have firmly established the role of CD4+ T cells, and particularly of Th1 phenotype, as the principal mediators of SK immunopathology. However, with the recent discovery of IL-17A and Th17 cells, the role of this cytokine as well as Th17 cells remains to be further defined. Recently it was shown that the normal cornea expresses VEGF-A, however its biological activity is impeded by its binding to a soluble form of VEGF-A receptor-1 (sVEGFR-1). Past studies have implicated the role of vascular endothelial growth factor-A (VEGF-A) in HSV induced corneal angiogenesis, however the source of VEGF-A as well as molecular mechanisms, particularly in the context of VEGF-A/sVEGFR-1 balance during HSV infection, are poorly understood.

The first part of this dissertation (I) reviews past literature on HSV induced corneal SK immunopathology. It focuses on the understanding of HSV-1 induced events that particularly results in corneal angiogenesis as well as tissue damage mediated by different type of cells as well as their secreted products. The next three parts (II-IV) focus on the mechanisms of HSV induced corneal angiogenesis as well as the relative role of Th1 and Th17 cells in SK immunopathology. Results in part II focuses on the relative role of IFN-γ/IL-17 as well as Th1/Th17 cells in HSV induced corneal immunopathology. The third section evaluate the significance of VEGF-A/sVEGFR-1 balance in HSV induced corneal neovascularization. Results in part IV focus on the role of IL-17A in altering the balance between VEGF-A and sVEGFR-1 post ocular HSV infection and subsequent corneal angiogenesis.

Collectively these studies identified novel mechanisms by which HSV infection of the cornea leads to the development of angiogenesis as well as corneal tissue damage and subsequent SK immunopathology, the most common cause of infectious blindness in the Western World.

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