Neovascularization and lymphangiogenesis are undesirable events that often transpire in the normally avascular cornea as a result of inflammation. As a consequence, visual acuity can be compromised and in the case of infection, an adaptive immune response ensues through the """"""""education"""""""" of effector cells within the draining lymph nodes. In response to virus infection of the cornea, a strong angiogenic response has been noted with new blood vessel growth within 7-10 days post infection in BALB/c mice. We have found lymphangiogenesis also occurs in response to acute herpes simplex virus type 1 (HSV-1) infection of the cornea in wild type (WT) C57BL/6 mice. However, unlike the corneal transplant model, we have found lymphatic vessel development in response to ocular HSV-1 infection does not require monocyte or macrophages. Furthermore, in this model of ocular HSV-1 infection lymphangiogenesis is dependent on vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) ligands but not VEGF receptor 3 ligands implicating VEGF-A and possibly placental growth factor. This is a unique finding for lymphangiogenesis in the cornea and one we wish to pursue. Specifically, we would like to test the hypothesis that HSV-1-mediated lymphangiogenesis occurs thru VEGF-A expression by HSV-1-infected epithelial cells and the lymphatic vessels created are functional and contribute to the generation of the adaptive immune response to HSV- 1. In order to test the hypothesis, two specific aims are proposed:
Specific aim 1 will address the role of VEGF-A in virus-induced lymphangiogenesis by identifying the cells that express VEGF-A longitudinally, determine the mechanism involved in VEGF-A expression, and define the contribution of other factors (e.g., IL-6, VEGF-C, and VEGF- D) to lymphangiogenesis following HSV-1 infection.
Specific aim 2 will address the functionality of the newly created lymphatic vessels by identifying the cells that traffic from the cornea to the draining lymph nodes at times post infection and determine the antigen-driven response of lymph node cells obtained from HSV-1-infected mice that either do or don't express corneal lymph vessels. In accomplishing these goals, we should eludicate the contribution of factors that drive HSV-1-induced corneal lymphangiogenesis and define the role of the lymphatic vessels in the generation of the adaptive immune response critical for ensuing stromal keratitis.
The identification of mechanism(s) associated with lymphangiogenesis may highlight novel molecules/pathways that significantly contribute to the development of lymphatic vessels as well as their contribution to the development of the adaptive immune response. Since T cells are associated with the development and severity of stromal keratitis, the identification of additional pathways that influence the development of effector T cells may provide targets to suppress the disease and preserve visual acuity.
|Wuest, Todd R; Carr, Daniel J J (2010) VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. J Exp Med 207:101-15|