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D. J. Carr, T. Wuest; HSV-1-Induced Corneal Lymphangiogenesis Requires Expression of Type I Interferon Receptor (CD118). Invest. Ophthalmol. Vis. Sci. 2008;49(13):822.
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To identify factors and cells that contribute to the development of lymphatic vessels in the cornea in response to herpes simplex virus type 1 (HSV-1) infection.
C57BL/6 wild type (WT) and type I interferon receptor deficient (CD118-/- on a C57BL/6 background) mice were infected with HSV-1 (1,000 plaque forming units/eye, strain McKrae) following corneal scarification. At times post infection, mice were exsanguinated and the corneas and draining lymph nodes (DLN, mandibular and cervical) were removed and analyzed for LYVE-1+ cells (cornea) as well as hematopoietic-derived cells including macrophages, granulocytes, NK cells, NKT cells, and T (CD4+ and CD8+) cells (cornea and DLN) by confocal microscopy and flow cytometry. Clodronate treatment included 8 microliters of suspension applied three days prior to, at the time of, and 2 and 4 days post infection administered in the conjunctiva. Eyes were harvested at day 5 post infection and corneas assessed for LYVE-1+ expression by confocal microscopy.
Following HSV-1 infection, WT mouse corneas showed progressive lymphatic vessel development from the limbus toward the viral-induced lesions over the duration of acute infection (day 7 post infection). By comparison, lymphatic vessel development was evident for the first 3 days post infection in CD118-/- mice. However, by day 5 post infection, lymphatic vessels were nearly absent including those found in the limbus region which associated with a significant loss (80%) of F4/80+ macrophages but a significant increase in neutrophils (F4/80-Gr1+) residing in the cornea in comparison to WT mice. Clodronate (liposome + clodronate) depletion of macrophages in WT mice modified the continuity of lymphatic vessel development but did not alter the area taken up by the lymphatic vessels in comparison to vehicle-treated (liposome + PBS) HSV-1-infected cornea from WT mice.
Corneal lymphangiogenesis in response to HSV-1 infection requires an intact type I interferon pathway. In addition to macrophages which appear to influence the integrity of the newly formed lymphatic vessels, other cells/factors also contribute toward corneal lymphangiogenesis following HSV-1 infection.
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