Inflammatory events along the visual axis invariably impair vision and the eye itself employs maneuvers to limit them, although not always successfully. For example, the most consequential outcome of ocular infection with Herpes simplex virus (HSV) is a chronic inflammatory reaction in the corneal stroma (stromal keratitis-SK). This lesion largely results from pro-inflammatory immune responses to infection which the host attempts to limit by several counter-inflammatory maneuvers. A prominent component of counter-inflammation is the activity of regulatory T cells (Treg), especially those that can be identified because they express the Foxp3 transcription factor which controls their regulatory activity. When the Treg response is absent or impaired SK lesions are more prolonged and consequential. Accordingly approaches that expand or increase the function of Treg represent potentially valuable forms of therapy. Unfortunately, the function of Treg can be unstable with the cells themselves losing their regulatory function and even taking on a pro-inflammatory role and then contributing to tissue damage. This instability, usually referred to as plasticity, can occur when Treg are in an inflammatory environment such as is usually the situation in SK. We anticipate that plasticity represents a problem during SK which needs to be controlled with appropriate therapeutic procedures. In the present proposal experiments are designed to formally demonstrate that Treg plasticity does occur in SK and to quantify its contribution to causing tissue damage in the eye. We shall also evaluate the ability of several therapeutic procedures that may block or even reverse Treg plasticity. A second series of experiments are designed to evaluate the therapeutic value of modifying the expression of some key microRNA molecules that we anticipate influence the severity of SK lesions. Finally, one aim of the proposal deals with the problem that during SK new blood vessel development occurs in the normally avascular cornea and this facilitates access of inflammatory components to the cornea and interferes with vision. A novel approach to control corneal neovascularization will be evaluated used as a single therapeutic approach or along with approaches found optimal to control Treg plasticity and /or microRNA modulation.

Public Health Relevance

Normal vision requires that the passage of light through the cornea to the retina not be interrupted. Inflammatory reactions along the visual axis such as that which can occur in the corneal stroma following herpes simplex virus (HSV) infection impairs vision. This proposal deals with approaches that serve to minimize the impact of inflammatory reactions caused by HSV infection by counteracting cellular and angiogenic events which result in damage to the cornea. Our studies could produce novel therapies useful to preserve vision.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Mckie, George Ann
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University of Tennessee Knoxville
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Rajasagi, Naveen K; Rouse, Barry T (2018) Application of our understanding of pathogenesis of herpetic stromal keratitis for novel therapy. Microbes Infect 20:526-530
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