Date of Award

12-2015

Degree Type

Thesis

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T. Rouse

Committee Members

Melissa Kennedy, Baek Seung, Jonathan Wall

Abstract

Herpetic stromal keratitis [HSK] is an immunoinflammatory corneal lesion caused by Herpes simplex virus type 1 [HSV] infection. SK is usually the consequence of virus reactivation from latency in the trigeminal ganglion. Studies in animal models have revealed that SK lesions are orchestrated mainly by CD4+T cells that infiltrate the corneal stroma. However, prior to this immunoinflammatory phase, multiple events occur that set the stage for subsequent pathology. These include production of cytokines and chemokines, infiltration of innate immune cells and neovascularization of the avascular cornea.

The first part of this dissertation reviews literature regarding the current understanding of human and murine SK pathogenesis, critical events and treatments. In chapter I we describe the role of Robo 4 [R4] receptor on the development of neovascularization [CV] in SK. We found that compared to wild type animals [WT], mice lacking R4 due to R4 gene knockout [R4 KO], had increased CV after HSV corneal infection. In addition, the administration of soluble extracellular domain of R4 [sR4] reduced angiogenesis in HSV infected WT mice.

The chapter II of this dissertation evaluates the role of Nod like receptor 3 [NLRP3] in driving the early inflammatory events that occur in HSV infected corneas. We found that compared to WT animals, mice lacking NLRP3 due to NLRP3 gene knockout [NLRP3-/-],had early onset of the disease and more severe SK lesions after HSV corneal infection.

In this thesis, experiments were designed to explore molecular and cellular events that occur during the early stages in SK. These results allowed us to uncover a new pathway implicated in angiogenesis as well as new pathogen recognition receptor involved in inflammation. Our findings serve as guidelines for future development of more efficient prophylactic and therapeutic strategies.

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