Keratitis caused by herpes simplex virus (HSV) infection remains a troublesome ocular disease that can result in blindness. Effective vaccines against HSV that can either prevent or modify the severity of disease expression neither exist nor are on the horizon. About 20% of keratitis cases result in chronic inflammatory reactions in the stroma. These stromal keratitis (SK) lesions are usually managed by prolonged treatment regimens that are often unsatisfactory. Improved treatment approaches are required. These need to inhibit steps in the pathogenesis of SK that are responsible for tissue damage and to stimulate the activity, or provide surrogates, of host components responsible for healing and repair of the cornea. Identifying events in SK pathogenesis that are accessible for therapy can be accomplished most effectively using animal models of the human disease, all of which unfortunately have their shortfalls. We use the tractable primary ocular infection model in mice where the pathogenesis of lesion expression has many similarities to the human disease. From past studies, it appears that the most accessible steps for therapeutic management in the pathogenesis of SK are to: a) prevent events that initiate the influx of inflammatory cells to the stroma, b) counteract the development and extent of corneal neovascularization (CV) that both facilitates inflammatory cell entrance and also contributes to visual impairment and c) remove and/or blunt the function and products of inflammatory cell types responsible for causing tissue damage in the stroma, and expand events that are counter-inflammatory and promote resolution. Our proposed research is to understand at a fundamental level how the essential step of CV is triggered by HSV infection and can be controlled by appropriate forms of therapy. These studies will focus on the role that the cytokine IL-17A plays in the stimulation of new blood vessel formation and on approaches that can be used to inhibit the angiogenic effects of IL-17A. We shall also determine how the CV responses to the major angiogenic factor VEGF are regulated by events that include vessel stabilizing ligand/receptor interactions and micro RNA expression in VEGF responding cells. These observations are expected to result in the design of new therapies that control the extent of CV. Additional studies are designed to further define the role of neutrophils and proinflammatory T cells in orchestrating SK and the use of therapies that counteract their activities. These therapies will include derivatives of omega-3 polyunsaturated fatty acids such as resolvins and protectins which are both anti-inflammatory and promote tissue repair. We shall also use drugs that activate aryl hydrocarbon receptors expressed by activated T cells, which should inhibit the inflammatory activity of such cells as well as expand the representation of regulatory T cells.
The final Aim will be to use drug combinations that target different steps in SK pathogenesis which are expected to have improved efficacy compared to single therapies to control disease severity and mediate tissue healing.

Public Health Relevance

Stromal keratitis 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 for control and treatment. This application, using an animal model system, will identify steps in the pathogenesis of stromal keratitis that are accessible to novel treatment procedures and will determine if combinations of drugs that target different steps of the disease process will be a superior approach for disease control!

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005093-30
Application #
8600274
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
1984-09-30
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
30
Fiscal Year
2014
Total Cost
$424,924
Indirect Cost
$130,727
Name
University of Tennessee Knoxville
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
003387891
City
Knoxville
State
TN
Country
United States
Zip Code
37996
Bhela, Siddheshvar; Mulik, Sachin; Reddy, Pradeep B J et al. (2014) Critical role of microRNA-155 in herpes simplex encephalitis. J Immunol 192:2734-43
Sharma, Shalini; Rajasagi, Naveen K; Veiga-Parga, Tamara et al. (2014) Herpes virus entry mediator (HVEM) modulates proliferation and activation of regulatory T cells following HSV-1 infection. Microbes Infect 16:648-60
Gimenez, Fernanda; Suryawanshi, Amol; Rouse, Barry T (2013) Pathogenesis of herpes stromal keratitis--a focus on corneal neovascularization. Prog Retin Eye Res 33:1-9
Veiga-Parga, Tamara; Sehrawat, Sharvan; Rouse, Barry T (2013) Role of regulatory T cells during virus infection. Immunol Rev 255:182-96
Veiga-Parga, Tamara; Gimenez, Fernanda; Mulik, Sachin et al. (2013) Controlling herpetic stromal keratitis by modulating lymphotoxin-alpha-mediated inflammatory pathways. Microbes Infect 15:677-87
Mulik, Sachin; Sharma, Shalini; Suryawanshi, Amol et al. (2011) Activation of endothelial roundabout receptor 4 reduces the severity of virus-induced keratitis. J Immunol 186:7195-204
Rajasagi, Naveen K; Reddy, Pradeep B J; Suryawanshi, Amol et al. (2011) Controlling herpes simplex virus-induced ocular inflammatory lesions with the lipid-derived mediator resolvin E1. J Immunol 186:1735-46
Suryawanshi, Amol; Veiga-Parga, Tamara; Rajasagi, Naveen K et al. (2011) Role of IL-17 and Th17 cells in herpes simplex virus-induced corneal immunopathology. J Immunol 187:1919-30
Sharma, Shalini; Mulik, Sachin; Kumar, Naveen et al. (2011) An anti-inflammatory role of VEGFR2/Src kinase inhibitor in herpes simplex virus 1-induced immunopathology. J Virol 85:5995-6007
Rouse, Barry T; Lukacher, Aron E (2010) Some unmet challenges in the immunology of viral infections. Discov Med 10:363-70

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