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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY005093-35
Application #
9603734
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
1984-09-30
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
35
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Tennessee Knoxville
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
003387891
City
Knoxville
State
TN
Country
United States
Zip Code
37916
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
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
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
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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