Our laboratory has been studying the role that Fas and Fas ligand play in corneal transplantation and have published several manuscripts detailing the importance of this interaction to the success of corneal allografts and the prevention of neovascularization of the cornea. However, the role that these apoptotic molecules play in herpetic eye disease remains to be fully delineated. The only report on this subject used a virus-mouse strain combination that does not produce significant disease. Thus the precise role that apoptotic molecules play in either causing or preventing HSV-1-mediated ocular disease is not clear. In order to bring more clarity to this situation, we performed preliminary studies wherein we infected BALB/c, and BALB-lpr (Fas mutants), and BALB-gld (Fas Ligand mutants) mice with the KOS strain of HSV-1 as well as C57BL/6 and its mutants with the McKrae strain of HSV-1, and monitored both corneal disease and shedding of virus from the ocular surface. Our observations indicate that mice that express a mutation in the Fas (CD95) gene had significantly worse HSK, and periocular disease, than did either wild type BALB/c or B6 mice. Gld mutants of these mouse strains were either no different than wild-type (BALB/c) or displayed an intermediated disease phenotype. Preliminary results also suggest that virus might persist in peripheral tissues slightly longer in BALB-lpr mice than in wild type controls, but similar persistence is also noted in BALB-gld mice. Suggesting that the disease phenotype in lpr mice might is not simply due to viral persistence, but that other mechanisms are involved. In order to better define the role that apoptotic molecules have during herpetic stromal keratitis we propose: To determine the specific contributions of Fas and FasL to ocular disease, protection from neuropathology, growth of virus, and maintenance of viral latency. Secondly, since we know that recurrent eye disease is not the same as primary HSK, we will perform similar studies in a recurrent model of HSK to evaluate the role of Fas and FasL in this form of the disease. We will also explore the efficacy of treating mice with a soluble form of Fas ligand as a means of more effectively controlling HSV-1 initiated inflammation. We believe these studies will enable us to better understand the role that the Fas-Fas ligand interaction plays during infectious disease of the cornea.

Public Health Relevance

The studies in this application are designed to better understand what mechanisms are involved in controlling the entry of immune cells (inflammation) into the cornea following infection with herpes simplex virus. This is important because the more inflammation that occurs the worse will be damage to the cornea. In addition, we will test a potential therapy that is designed to further control and possibly prevent inflammation.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Shen, Grace L
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Saint Louis University
Schools of Medicine
Saint Louis
United States
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Azher, Tayaba N; Yin, Xiao-Tang; Tajfirouz, Deena et al. (2017) Herpes simplex keratitis: challenges in diagnosis and clinical management. Clin Ophthalmol 11:185-191
Tajfirouz, Deena; West, Devin M; Yin, Xiao-Tang et al. (2017) CXCL9 compensates for the absence of CXCL10 during recurrent Herpetic stromal keratitis. Virology 506:7-13
Rogge, Megan; Yin, Xiao-Tang; Godfrey, Lisa et al. (2015) Therapeutic Use of Soluble Fas Ligand Ameliorates Acute and Recurrent Herpetic Stromal Keratitis in Mice. Invest Ophthalmol Vis Sci 56:6377-86
Yin, Xiao-Tang; Keadle, Tammie L; Hard, Jessicah et al. (2015) Impaired Fas-Fas Ligand Interactions Result in Greater Recurrent Herpetic Stromal Keratitis in Mice. J Immunol Res 2015:435140
West, Devin M; Del Rosso, Chelsea R; Yin, Xiao-Tang et al. (2014) CXCL1 but not IL-6 is required for recurrent herpetic stromal keratitis. J Immunol 192:1762-7
Stuart, Patrick M; Keadle, Tammie L (2012) Recurrent herpetic stromal keratitis in mice: a model for studying human HSK. Clin Dev Immunol 2012:728480
Morris, Jessica E; Zobell, Stephanie; Yin, Xiao-Tang et al. (2012) Mice with mutations in Fas and Fas ligand demonstrate increased herpetic stromal keratitis following corneal infection with HSV-1. J Immunol 188:793-9