Long-term consequences of topical dexamethasone treatment during acute corneal HSV-1 infection on the immune system

Abstract

Herpes simplex virus type 1 (HSV-1) is a leading cause of neurotrophic keratitis (NTK). NTK is characterized by decreased corneal sensation from damage to the corneal sensory fibers. We have reported on the regression of corneal nerves and their function during acute HSV-1 infection. That nerve loss is followed by an aberrant process of nerve regeneration during the latent phase of infection that lacks functional recovery. We recently showed the elicited immune response in the infected cornea, and not viral replication itself, is part of the mechanism responsible for the nerve degeneration process after infection. Specifically, we showed infected corneas topically treated with dexamethasone (DEX) significantly retained both structure and sensitivity of the corneal nerve network in comparison to mice treated with control eye drops, consistent with decreased levels of proinflammatory cytokines and reduced influx of macrophages and CD8 T cells into the cornea. This study was undertaken to analyze the long-term effect of such a localized, immunosuppressive paradigm (DEX drops on the cornea surface during the first 8 d of HSV-1 infection) on the immune system and on corneal pathology. We found the profound immunosuppressive effect of DEX on lymphoid tissue was sustained in surviving mice for up to 30 d postinfection (p.i.). DEX treatment had prolonged effects, preserving corneal innervation and its function and blunting neovascularization, as analyzed at 30 d p.i. Our data support previously reported observations of an association between the persistent presence of inflammatory components in the latently infected cornea and structural and functional nerve defects in NTK.

Colony Stimulating Factor-1 Receptor Expressing Cells Infiltrating the Cornea Control Corneal Nerve Degeneration in Response to HSV-1 Infection

“… 36 – 38 Upon systemic treatment with the dimerizer drug AP20187 and subsequent ocular infection with HSV-1, mouse tissues were analyzed to address the impact of the macrophage lineage in nerve regression, and to identify factors and downstream signaling pathways that might be implicated in the neurodegenerative mechanism. Our results consolidate previous evidence on the cross talk between the immune and nervous systems during nerve degeneration in the cornea 18 , 19 , 21 , 22 , 24 and suggest a mechanistic axis comprising a corneal influx of macrophages, increased inflammatory cytokines including IL-6, and activation of the gp130/signal transducer and activator of transcription 3 (STAT3) signaling pathway in the process of virus-induced NTK.…”

“…Topical delivery of DEX was performed as previously described. 18 , 19 Starting at 2 hours PI, nonanesthetized mice were held by the scruff of the neck, and topically delivered a drop of 0.1% DEX ophthalmic solution (Bausch+Lomb, Inc., Tampa, FL, USA; #001-000050-00) onto their corneas. Control treatments (VEH) were done by applying lubricant eye drops (Allergan, Inc., Irvine, CA, USA) onto each cornea.…”

“…Despite the increasing interest on the research topic of corneal innervation in regards to HSV-1 infection, 17 – 23 the mechanisms behind the changes in the distribution and function of corneal nerves as a consequence of viral infection remain to be addressed. Indeed, the identification of target cells, factors, and their downstream signaling pathways has the potential to expand our understanding of a broad spectrum of peripheral neuropathies that develop in inflammatory disease settings (e.g., diabetes mellitus, bacterial infection, and chemical burns).…”

Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia

“…At 3-4 weeks post-Tam treatment, Cx3cr1-cre/ERT2 + ; NuTRAP + mice were systemically administered 5 mg/kg LPS 31 (#L2262, 1 mg/ml stock solution; Millipore Sigma) or vehicle (PBS) by ip injection. Blood was collected from the facial vein of mice at 4h and 24h post-LPS treatment, using a 5-mm sterile Goldenrod animal lancet (MEDIpoint, Mineaola, NY), mixed with 5µl 0.5M EDTA to prevent coagulation 39 , and centrifuged at 1,000 x g for 10 min for plasma collection. At 24h post LPS treatment, mice were euthanized and a sagittal slice circumscribing the medial line of their brains was harvested and homogenized in RIPA buffer supplemented with 1X Halt TM protease inhibitor cocktail (#78437; ThermoFisher Scientific, Grand Island, NY) by sonication.…”

Stress Hormones Epinephrine and Corticosterone Selectively Modulate Herpes Simplex Virus 1 (HSV-1) and HSV-2 Productive Infections in Adult Sympathetic, but Not Sensory, Neurons

“…In addition, treatment of the immortalized neuronal cell line PC12 and human gingival fibroblasts with dexamethasone (DEX), a GCR agonist, resulted in increases in HSV-1 DNA replication and infectious virus yields during productive infection (13,14). Furthermore, dexamethasone treatment increased the mortality of mice acutely infected with HSV-1 (15), significantly increased HSV-1 ocular shedding and corneal ulceration in latently infected rabbits (16), consistently induced the reactivation of bovine herpesvirus 1 in calves (17), and could induce HSV-1 keratitis in humans (18). Taken together, the stress hormones epinephrine and corticosterone have impacts on acute and latent infections with HSV-1 and HSV-2.…”