Abstract
Purpose :
HSK is a potentially blinding corneal disease caused by herpes simplex virus type 1 (HSV-1) infection, which manifests in both humans and mice as corneal edema, opacity, neovascularization, and hypoesthesia. After primary corneal infection, the virus gains access to the trigeminal ganglion through the ophthalmic branch of the trigeminal nerve and establishes lifelong latency. The virus can reactivate under certain circumstances and travel to the cornea to cause recurrent HSK (rHSK). We have found that the replacement of corneal sensory nerves with sympathetic nerves in murine primary HSK led to severe and diffuse inflammation, and CD4+ T cells and myeloid cells, through the production of vascular endothelial growth factor A, maintained the disrupted corneal nerve landscape. Here, we aimed to identify whether this mechanism governs rHSK.
Methods :
Male and Female C57BL/6 and NIH mice were infected with HSV-1 McKrae strain and were protected from primary infection by intraperitoneal injections of pooled human serum. The eyes were then exposed to 170 (NIH mice) or 250 (C57BL/6 mice) mJ/cm2 of UV-B light. Groups of mice received anti-CD4 antibody (150ug, once a week) to deplete CD4+ T cells or appropriate control. Mice were monitored for corneal opacity, neovascularization, and blink reflex. Virus reactivation was determined by eye swabbing for live virus and IHC staining for HSV-1 antigens. Corneal whole mounts were stained for β III tubulin, tyrosine hydroxylase, and substance P to define sympathetic and sensory nerves, respectively.
Results :
No virus was detected in mice that did not receive U.V. irradiation. Live virus was detected in 30% of both strains of mice after U.V. irradiation. IHC study detected HSV-1 antigens in 100% of the corneas. Mice developed progressive HSK and eventually lost blink reflex with a significant reduction in corneal sensory nerve density. Different from the primary HSK, the invasion of sympathetic nerves in the rHSK cornea was sectorial. Finally, depletion of CD4+ T cells correlated with less severe disease, more sensory nerve retention, and less dense sympathetic innervation of the cornea.
Conclusions :
U.V. light-mediated viral reactivation from latency is more consistent than previously realized. CD4+ T cell-dependent induction of sympathetic innervation of the cornea acts both in the primary HSK and rHSK.
This is a 2021 ARVO Annual Meeting abstract.