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 #
2R01EY005093-29A1
Application #
8386630
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
1984-09-30
Project End
2016-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
29
Fiscal Year
2013
Total Cost
$469,808
Indirect Cost
$144,808
Name
University of Tennessee Knoxville
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
003387891
City
Knoxville
State
TN
Country
United States
Zip Code
37996
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
Bhela, Siddheshvar; Rouse, Barry T (2018) Are miRNAs critical determinants in herpes simplex virus pathogenesis? Microbes Infect 20:461-465
Sehrawat, Sharvan; Kumar, Dhaneshwar; Rouse, Barry T (2018) Herpesviruses: Harmonious Pathogens but Relevant Cofactors in Other Diseases? Front Cell Infect Microbiol 8:177
Varanasi, Siva Karthik; Rajasagi, Naveen K; Jaggi, Ujjaldeep et al. (2018) Role of IL-18 induced Amphiregulin expression on virus induced ocular lesions. Mucosal Immunol 11:1705-1715
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
Varanasi, Siva Karthik; Reddy, Pradeep B J; Bhela, Siddheshvar et al. (2017) Azacytidine Treatment Inhibits the Progression of Herpes Stromal Keratitis by Enhancing Regulatory T Cell Function. J Virol 91:
Varanasi, Siva Karthik; Donohoe, Dallas; Jaggi, Ujjaldeep et al. (2017) Manipulating Glucose Metabolism during Different Stages of Viral Pathogenesis Can Have either Detrimental or Beneficial Effects. J Immunol 199:1748-1761
Bhela, Siddheshvar; Varanasi, Siva Karthik; Jaggi, Ujjaldeep et al. (2017) The Plasticity and Stability of Regulatory T Cells during Viral-Induced Inflammatory Lesions. J Immunol 199:1342-1352
Gimenez, Fernanda; Bhela, Siddheshvar; Dogra, Pranay et al. (2016) The inflammasome NLRP3 plays a protective role against a viral immunopathological lesion. J Leukoc Biol 99:647-57
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

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