Neovascularization in the normally avascular cornea can lead to a compromised visual axis. Within the term """"""""neovascularization"""""""" is a blood component referred to as hemangiogenesis and a lymphatic component referred to as lymphangiogenesis. Relative to herpes simplex virus type 1 (HSV-1) infection, only hemangiogenesis has been investigated. Recently, we have initiated a study on lymphangiogenesis following corneal infection with HSV-1 and discovered this process precedes hemangiogenesis. More importantly, we have discovered the genesis of lymphatic vessels in the cornea proper in response to HSV-1 infection operates thru a unique pathway distinct from what has been described following corneal transplantation. Specifically, we have found a robust vascular endothelial growth factor (VEGF) A response by corneal epithelium infected with HSV-1 elicits lymphangiogenesis thru a VEGF receptor 2 (VEGFR2)-mediated pathway. This process is independent of VEGF C, VEGF receptor 3, or monocytes/macrophages. We have also found the newly created lymphatic vessels are capable of transporting soluble antigen to the draining lymph node independent of hemangiogenesis. However, what remains unknown is the contribution of the newly created lymphatic conduit to the host immune response within the draining lymph node as well as other inflammatory mediators that contribute to corneal lymphangiogenesis. We hypothesize lymphatic vessel development driven principally by VEGF A and contributing pro-inflammatory molecules generated locally in response to infection are critical for the induction of the adaptive immune response found in the draining lymph node reflected by the severity in the development of herpetic stromal keratitis of HSV-1 infected mice. To address this hypothesis, two specific aims are proposed:
Specific aim 1 will address the impact of viral replication and pro- inflammatory cytokine expression on corneal lymphangiogenesis following HSV-1 infection. In addition, trafficking of leukocyte subpopulations and antigen will be monitored as well.
Specific aim 2 will address the significance of lymphangiogenesis relative to the genesis of the adaptive immune response in the draining lymph node and development of stromal keratitis following HSV-1 infection. It will further address the role of virus-induced VEGF A production on the production of CD4+ and CD8+ T effector cells that contribute in viral surveillance and corneal pathogenesis. It is anticipated in accomplishing these goals, we will eludicate the contribution of pro-lymphangiogenesis factors in the generation of the adaptive immune response critical for the ocular pathology that includes the debilitating and sometimes blinding stromal keratitis.

Public Health Relevance

The role of lymphangiogenesis as a central force driving the adaptive immune response to ocular herpes simplex virus type 1 (HSV-1) infection has not been explored. In combination with HSV-1-induced vascular endothelial growth factor (VEGF)-A, a potent immunomodulatory molecule, it is anticipated the study will identify how HSV-1-induced lymphangiogenesis and VEGF-A production influence the immune response to the infection and in so doing, lead to a treatment strategy to alter the host response, attenuate the development of herpetic stromal keratitis, and preserve the visual axis.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Anterior Eye Disease Study Section (AED)
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Mckie, George Ann
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University of Oklahoma Health Sciences Center
Schools of Medicine
Oklahoma City
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Royer, Derek J; Elliott, Michael H; Le, Yun Z et al. (2018) Corneal Epithelial Cells Exhibit Myeloid Characteristics and Present Antigen via MHC Class II. Invest Ophthalmol Vis Sci 59:1512-1522
Gurung, H R; Carr, M M; Bryant, K et al. (2018) Fibroblast growth factor-2 drives and maintains progressive corneal neovascularization following HSV-1 infection. Mucosal Immunol 11:172-185
Chucair-Elliott, Ana J; Gurung, Hem R; Carr, Meghan M et al. (2017) Colony Stimulating Factor-1 Receptor Expressing Cells Infiltrating the Cornea Control Corneal Nerve Degeneration in Response to HSV-1 Infection. Invest Ophthalmol Vis Sci 58:4670-4682
Royer, Derek J; Carr, Meghan M; Chucair-Elliott, Ana J et al. (2017) Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice. J Virol 91:
Chucair-Elliott, Ana J; Carr, Meghan M; Carr, Daniel J J (2017) Long-term consequences of topical dexamethasone treatment during acute corneal HSV-1 infection on the immune system. J Leukoc Biol 101:1253-1261
Gurung, Hem R; Carr, Meghan M; Carr, Daniel J J (2017) Cornea lymphatics drive the CD8+ T-cell response to herpes simplex virus-1. Immunol Cell Biol 95:87-98
Royer, Derek J; Carr, Meghan M; Gurung, Hem R et al. (2017) The Neonatal Fc Receptor and Complement Fixation Facilitate Prophylactic Vaccine-Mediated Humoral Protection against Viral Infection in the Ocular Mucosa. J Immunol 199:1898-1911
Royer, Derek J; Gurung, Hem R; Jinkins, Jeremy K et al. (2016) A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity. J Virol 90:5514-5529
Chucair-Elliott, Ana J; Jinkins, Jeremy; Carr, Meghan M et al. (2016) IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection. Am J Pathol 186:2665-78
Royer, D J; Carr, D J J (2016) A STING-dependent innate-sensing pathway mediates resistance to corneal HSV-1 infection via upregulation of the antiviral effector tetherin. Mucosal Immunol 9:1065-75

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