HSV-1 Targets Lymphatic Vessels in the Eye and Draining Lymph Node of Mice Leading to Edema in the Absence of a Functional Type I Interferon Response

Abstract

Herpes simplex virus type-1 (HSV-1) induces new lymphatic vessel growth (lymphangiogenesis) in the cornea via expression of vascular endothelial growth factor by virally infected epithelial cells. Here, we extend this observation to demonstrate the selective targeting of corneal lymphatics by HSV-1 in the absence of functional type I interferon (IFN) pathway. Specifically, we examined the impact of HSV-1 replication on angiogenesis using type I IFN receptor deficient (CD118(-/-)) mice. HSV-1-induced lymphatic and blood vessel growth into the cornea proper was time-dependent in immunocompetent animals. In contrast, there was an initial robust growth of lymphatic vessels into the cornea of HSV-1-infected CD118(-/-)mice, but such vessels disappeared by day 5 postinfection. The loss was selective as blood vessel integrity remained intact. Magnetic resonance imaging and confocal microscopy analysis of the draining lymph nodes of CD118(-/-) mice revealed extensive edema and loss of lymphatics compared with wild-type mice. In addition to a loss of lymphatic vessels in CD118(-/-) mice, HSV-1 infection resulted in epithelial thinning associated with geographic lesions and edema within the cornea, which is consistent with a loss of lymphatic vasculature. These results underscore the key role functional type I IFN pathway plays in the maintenance of structural integrity within the cornea in addition to the anti-viral characteristics often ascribed to the type I IFN cytokine family.

A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity

“…Infectious or traumatic insults involving the cornea can compromise its immunoprivileged status and consequently permit substantial pathological sequelae, including leukocyte infiltration, corneal edema, hypoesthesia (sensation loss), and neovascularization. Following HSV-1 infection in mice, pathological corneal edema and neovascularization ensue commensurate with epithelial thinning within geographic corneal lesions (1,2,44). Similar to corneal neovascularization, hypoesthesia is a hallmark of herpes stromal keratitis in mice and humans and results from denervation of the epitheliumassociated subbasal mechanosensory nerve fibers (40,45,46).…”

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

“…5A). We have previously shown that HSV-1 McKrae gains access to the draining lymph nodes and disrupts adaptive immune responses in CD118 Ϫ/Ϫ mice (62,66,67); however, this is not observed with HSV-1 0ΔNLS or KOS-GFP (Fig. 4).…”

“…6C). Virulent HSV-1 strains such as McKrae have been shown to infect every layer of the cornea in CD118 Ϫ/Ϫ mice and destroy lymphatic vessels during acute infection (29,67). The acute death of these animals pursuant to HSV-1 infection has rendered investigating late pathology in the eye impossible until now.…”

The use of human cornea organotypic cultures to study herpes simplex virus type 1 (HSV-1)-induced inflammation

“…Anpt2 is reportedly generated by macrophages and lymphatic endothelial cells in the cornea [22]. It is tempting to speculate the loss of Angpt2 levels may be due to the depletion of macrophages and/or lymphatic endothelium of which the latter is specifically targeted in the presence of high viral content [23] and the former has been found in the anterior stroma of human corneas [24]. At no time was IL-17 detected which suggests that the influx of inflammatory cells including neutrophils [25] are a likely source of this pro-inflammatory cytokine in response to HSV-1 infection.…”