Stromal Keratitis (SK) caused by herpes simplex virus (HSV) infection remains a troublesome ocular disease that can result in blindness. Vaccines to control SK are unavailable and none are on the horizon. Consequently SK lesions are usually managed by prolonged treatment regimens that are often not ideal and improved treatment approaches are needed. Novel treatments could emerge by targeting key events in SK pathogenesis. To study accessible steps for therapies primary infection model in mice is the most convenient to use. The proposed research will evaluate the efficacy of recently discovered anti-inflammatory and resolution inducing lipid mediators derived from omega-3-polyunsaturated fatty acids (omega-3-PUFA) for their ability to control the severity of HSV induced ocular lesions when administered at different times post infection.
In aim 1 of this proposal, we shall use both in vivo and in vitro approaches to compare the effectiveness of the drug resolvin D1 given topically in the soluble form with the same drug given in the form of nanoparticles to inhibit clinical disease and minimize inflammatory events. A comparison of the efficacy of resolvin therapy with topical corticosteroids will also be done. We also expect to provide a cell and molecular mechanistic explanation for our observations.
In aim 2, we will also investigate the nature of microRNA changes that occur in response to HSV infection and therapy with resolvin drugs. We shall examine the role of specific microRNAs associated with the production and function of resolution inducing lipid mediators in the SK model. If successful, our findings will provide novel means of controlling SK lesions that cause vision loss in humans.

Public Health Relevance

Stromal keratitis (SK) resulting from herpes simplex virus infection remains the most common infectious cause of blindness in the USA. There is a need to develop new approaches to complement and maybe replace some existing drugs to control and treat SK lesions. This proposal, using an animal model system, will define the relevance of novel anti-inflammatory and pro-resolving lipid mediators derived from Omega-3 polyunsaturated fatty acids, namely resolvin D1 and nanoparticles containing resolvin D1 in controlling stromal keratitis. Our proposed studies could represent a potential novel approach to resolve the lesions of SK.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Mckie, George Ann
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University of Tennessee Knoxville
Schools of Veterinary Medicine
United States
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Rajasagi, Naveen K; Bhela, Siddheshvar; Varanasi, Siva Karthik et al. (2017) Frontline Science: Aspirin-triggered resolvin D1 controls herpes simplex virus-induced corneal immunopathology. J Leukoc Biol 102:1159-1171
Rajasagi, Naveen K; Rouse, Barry T (2016) IL-2 complex treatment amplifies CD8+ T cell mediated immunity following herpes simplex virus-1 infection. Microbes Infect 18:735-746