Herpetic stromal keratitis (HSK) is a leading cause of infectious blindness in the United States. Visual loss most commonly results from recurrent stromal disease, as opposed to primary HSK and appears to be the result of immune-mediated corneal destruction. Most experimental models have focused on primary rather than recurrent keratitis. We study a model of recurrent HSK in inbred NIH mice that mimics many clinical and immunological features of recurrent HSK in humans. While current data indicates that primary and recurrent HSK are similar, there are significant differences in the clinical pathology, viral antigen distribution and cellular infiltration within the cornea, and responses to vaccine therapy suggesting that the immune responses in these two diseases is not identical. During the past 3+ years of the current grant we have reported: 1) That IL- 1 and TNFalpha are necessary for recurrent disease. 2) That there is a mixed population of Th1 and Th2 cells present in the corneas of mice with recurrent HSK. 3) That recurrent HSK has variable requirements for CD4 and CD8 T cells that depend on mouse strain. 4) That we can successfully ameliorate disease by vaccination with mutant HSV-1 viruses. Based on our results and what is known from others work we propose to further test the hypothesis that recurrent HSK is primarily mediated by CD4+ T cells of the Th1 phenotype. In order to test this hypothesis we will: (1) Determine the role that IL-6 and chemokines play in recurrent disease. (2) Determine which co stimulatory interactions are needed to activate and restimulate the cells that mediate recurrent HSK and whether therapeutic intervention targeting these interactions will ameliorate disease. (3) Characterize the immune response generated by vaccination with mutant strains of HSV-1 in mice both prior to (prophylactic) and after (therapeutic) infection with wild-type HSV-1 with an eye towards determining if that immune response involves the selective stimulation of Th2 cells. And to determine whether vaccination reduces the number of latently infected neurons. (4) Develop a mouse model using ovalbumin (OVA) expressing strains of HSV-1 and OVA-specific TCR transgenic T cells (DO-11.10, OT-I, OT-II) to characterize the activation, migration, cytokine profile, and possible tolerization protocols of viral pseudo-antigen specific T cells. The information derived from these studies will lead to a better understanding of the biology of recurrent HSK in mice and by extension human disease. Furthermore, these studies could possibly suggest more effective immunotherapies designed to ameliorate human HSK disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VISA (01))
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Shen, Grace L
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Washington University
Schools of Medicine
Saint Louis
United States
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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
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
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; Stuart, Patrick M; Rogge, Megan et al. (2012) Recurrent herpetic stromal keratitis in mice, a model for studying human HSK. J Vis Exp :e4276
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
Carr, Daniel J J; Austin, Bobbie A; Halford, William P et al. (2009) Delivery of Interferon-gamma by an adenovirus vector blocks herpes simplex virus Type 1 reactivation in vitro and in vivo independent of RNase L and double-stranded RNA-dependent protein kinase pathways. J Neuroimmunol 206:39-43
Ferguson, Thomas A; Stuart, Patrick M; Herndon, John M et al. (2003) Apoptosis, tolerance, and regulatory T cells--old wine, new wineskins. Immunol Rev 193:111-23
Keadle, Tammie L; Laycock, Keith A; Morris, Jessica L et al. (2002) Therapeutic vaccination with vhs(-) herpes simplex virus reduces the severity of recurrent herpetic stromal keratitis in mice. J Gen Virol 83:2361-5
Keadle, T L; Usui, N; Laycock, K A et al. (2000) IL-1 and TNF-alpha are important factors in the pathogenesis of murine recurrent herpetic stromal keratitis. Invest Ophthalmol Vis Sci 41:96-102