Date of Award

5-2008

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T. Rouse

Committee Members

Robert N. Moore, Steven J Kennel, Mark Y. Sangster

Abstract

Herpetic stromal keratitis (HSK) is an immunopathological and tissue destructive corneal lesion caused by herpes simplex virus (HSV) infection, which induces an intense inflammatory response and finally leads to blindness. Accumulating evidence using the murine model has shown that Th-1 phenotype CD4+ T cells orchestrating the inflammation mainly contribute to the immunopathological reaction in HSV-1 infected cornea. However, prior to CD4+ T cell infiltration into corneal lesions, various innate immune cells recruit and produce numerous inflammatory and angiogenic molecules into the corneal stroma those in turn drive the corneal immunopathology.

The first part (Part I) of this dissertation focuses on the understanding of HSV-1 induced immunoinflammatory processes in the cornea and trigeminal ganglia including the secondary lymphoid tissues. The next three parts (Part II-IV) focus on different inflammatory and anti-inflammatory mechanisms that are activated following virus infection in the cornea. Results in Part II evaluate the role of various Toll-like receptors (TLRs) in driving the early inflammatory events that occur in the HSV infected corneas. Thus, this part demonstrates that mainly TLR2 and to a lesser extent TLR9 ligand activity of HSV is important for driving SK pathology. Results of the third section show that HSV infection results in the up regulation of IL-23 that is needed for the survival of pathogenic Th-17 cells. The data show that mice lacking IL-23 were more susceptible to SK lesions and that the heightened lesion severity was attributed to higher IL-12 production and Th1 immune response in such animals. The fourth section describes the relative role of IL-10 and natural regulatory T cells (nTregs) as two independent anti-inflammatory mechanisms that are needed for controlling HSK lesions.

In this study, experiments were designed to understand the mechanisms involved in the induction and regulation of immunopathology in HSK and modulation of such processes could be useful in designing therapeutic for HSK.

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