Corneal Lymphatics & Adaptive Immunity

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 DESCRIPTION (provided by applicant): Herpes simplex virus type 1 (HSV-1) induces neovascularization in the avascular cornea including the genesis of blood and lymphatic components referred to as hemangiogenesis and lymphangiogenesis respectively. Clinically, angiogenesis of the central cornea has a detrimental impact on visual acuity and in many instances, the success of corneal engraftment following transplantation. Previously, we have found HSV-1 induces lymphangiogenesis following cornea infection that requires the local (i.e., epithelial cell) production of vascular endothelial growth factor (VEGF) A mediating its effects through VEGF receptor 2 (VEGFR2). Moreover, we found the immediate early gene-encoded protein ICP4 of HSV-1 drives expression of the VEGF A gene through Sp1 and (perhaps) EGR1 promoter sites. Consistent with these findings, corneal lymphangiogenesis does not act through toll-like receptors or require a MAP kinase pathway of induction. This is a novel observation unique to the pathogen. Newly acquired data included in this application demonstrates corneal neovascularization following HSV-1 infection proceeds at much more robust pace after the virus clears the cornea between day 10 and day 30 post infection (pi). During this time period, we have identified several pro- angiogenic factors in addition to VEGF A including interleukin (IL)-6, hepatocyte growth factor (HGF), and matrix metalloproteinase 9 (MMP9) that are up regulated and peak at day 14 pi. We have also identified cells including neutrophils, macrophages, inflammatory monocytes, and T cells that reside and are maintained in the cornea throughout the robust neovascularization period of the cornea post HSV-1 infection. Additional preliminary results suggest IL-6, HGF, and inflammatory monocytes are most closely associated with the progress in neovascularization of the cornea post virus clearance between days 10-30 pi. As such, we propose to test the hypothesis that IL-6 and HGF facilitate the development and maintain corneal lymphatic vessels upon clearance of HSV-1 (aim 1). In addition, preliminary results suggest the reduction in VEGF A expression and loss of lymphatic vessels in the cornea post HSV-1 infection significantly reduces the adaptive immune response to the pathogen resulting in a higher viral yield in the trigeminal ganglion. We hypothesize the reduced adaptive immune response is due to a loss of functional antigen presenting cells in the draining lymph node (aim 2). Collectively, the proposed experimental design will allow us to characterize corneal lymphangiogenesis relative to HSV-1 infection with the anticipated outcome of the identification of additional pro-angiogenic factors and pathways as candidate targets for therapeutic intervention.