Chemical sympathectomy increases susceptibility to ocular herpes simplex virus type 1 infection

Abstract

The cornea is one of the most highly innervated tissues in the mammalian host. We hypothesized changes to cornea innervation through chemical sympathectomy would significantly alter the host response to the neurotropic viral pathogen, herpes simplex virus type 1 (HSV-1) following ocular infection. Mice treated with 6-hydroxydopamine hydrobromide displayed reduced tyrosine hydroxylase-positive fibers residing in the cornea. Sympathectomized mice were also found to show a transient rise in virus recovered in infected tissues and succumbed to infection in greater numbers. Whereas there were no differences in infiltrating leukocyte populations including HSV-1-specific cytotoxic T lymphocytes in the infected tissue, an increase in substance P and a decrease in IFN-γ levels in the trigeminal ganglion but not brain stem of sympathectomized mice were noted. Sympathectomized mice treated with the neurokinin-1 receptor antagonist L703,606 had delayed mortality implicating the involvement of substance P in HSV-1-mediated death.

Sympathetic nervous system control of anti-influenza CD8+T cell responses

“…Because 6-OHDA treatment can greatly modify innate immune responses (13,16), this could contribute to the differences between our findings and those of Bonneau and colleagues (25). Using a different HSV model system in mice, Carr and colleagues (26) reported that 6-OHDA treatment before ocular infection does not significantly modify T CD8ϩ responses in draining lymph nodes.…”

“…As described by van Endert and colleagues (23), peptide determinants are rapidly liberated from the fusion protein by Ub-hydrolases and behave like cytosolic minigene products. 6-OHDA treatment increased the primary T CD8ϩ response to Ova 257-264 and to the immunodominant VV determinant B8R [20][21][22][23][24][25][26][27] (Fig. 2B).…”

Corneal nerves in health and disease

“…Activation of latent VZV causes inflammatory destruction of corneal nerves, 196 whereas inflammation-related neuropeptides can be beneficial in reducing herpetic keratopathies. Trigeminal and corneal sympathetic nervous system activity and increased interferon-γ levels ward off infection in mice, 212 thus preserving corneal nerves. Combination treatment with SP and IGF-1 completely resolves epithelial defects in neurotrophic keratopathy patients, though SP may worsen microbial keratitis by promoting excess inflammation.…”

“…Combination treatment with SP and IGF-1 completely resolves epithelial defects in neurotrophic keratopathy patients, though SP may worsen microbial keratitis by promoting excess inflammation. 72,212,230 Non-infectious disease processes, both corneal and systemic, also negatively affect corneal nerves.…”

Comparison of the Host Immune Response to Herpes Simplex Virus 1 (HSV-1) and HSV-2 at Two Different Mucosal Sites

“…Specifically, A5(ϩ) neurons support HSV-2 replication whereas KH10(ϩ) neurons support HSV-1 productive infection (3). Since A5(ϩ) neurons are noradrenergic (34) and KH10(ϩ) neurons are sensory in nature (8) and both adrenergic and sensory neuronal pathways influence the host immune response or sparing of neurons following HSV infection (14,35), it is not surprising that disparate immune responses to these two closely related but distinct viral pathogens ensue within the nervous system. A randomized, double-blind HSV vaccine trial utilizing glycoprotein D from HSV-2 (gD-2, with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant) was recently performed to test for efficacy against HSV-1 and HSV-2 genital disease and infection.…”