Murine Corneal Inflammation and Nerve Damage After Infection With HSV-1 Are Promoted by HVEM and Ameliorated by Immune-Modifying Nanoparticle Therapy

Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):282-291. doi: 10.1167/iovs.16-20668.


Purpose: To determine cellular and temporal expression patterns of herpes virus entry mediator (HVEM, Tnfrsf14) in the murine cornea during the course of herpes simplex virus 1 (HSV-1) infection, the impact of this expression on pathogenesis, and whether alterations in HVEM or downstream HVEM-mediated effects ameliorate corneal disease.

Methods: Corneal HVEM levels were assessed in C57BL/6 mice after infection with HSV-1(17). Leukocytic infiltrates and corneal sensitivity loss were measured in the presence, global absence (HVEM knockout [KO] mice; Tnfrsf14-/-), or partial absence of HVEM (HVEM conditional KO). Effects of immune-modifying nanoparticles (IMPs) on viral replication, corneal sensitivity, and corneal infiltrates were measured.

Results: Corneal HVEM+ populations, particularly monocytes/macrophages during acute infection (3 days post infection [dpi]) and polymorphonuclear neutrophils (PMN) during the chronic inflammatory phase (14 dpi), increased after HSV-1 infection. Herpes virus entry mediator increased leukocytes in the cornea and corneal sensitivity loss. Ablation of HVEM from CD45+ cells, or intravenous IMP therapy, reduced infiltrates in the chronic phase and maintained corneal sensitivity.

Conclusions: Herpes virus entry mediator was expressed on two key populations: corneal monocytes/macrophages and PMNs. Herpes virus entry mediator promoted the recruitment of myeloid cells to the cornea in the chronic phase. Herpes virus entry mediator-associated corneal sensitivity loss preceded leukocytic infiltration, suggesting it may play an active role in recruitment. We propose that HVEM on resident corneal macrophages increases nerve damage and immune cell invasion, and we showed that prevention of late-phase infiltration of PMN and CD4+ T cells by IMP therapy improved clinical symptoms and mortality and reduced corneal sensitivity loss caused by HSV-1.

MeSH terms

  • Animals
  • Biocompatible Materials / administration & dosage
  • Cornea / metabolism
  • Cornea / pathology
  • Cornea / virology
  • Disease Models, Animal
  • Eye Infections, Viral / diagnosis
  • Eye Infections, Viral / immunology
  • Eye Infections, Viral / therapy*
  • Flow Cytometry
  • Herpesviridae Infections / diagnosis
  • Herpesviridae Infections / immunology
  • Herpesviridae Infections / therapy*
  • Herpesvirus 1, Human / pathogenicity*
  • Immunity, Cellular
  • Immunohistochemistry
  • Immunotherapy / methods*
  • Injections, Intravenous
  • Keratitis, Herpetic / diagnosis
  • Keratitis, Herpetic / immunology
  • Keratitis, Herpetic / therapy*
  • Keratitis, Herpetic / virology
  • Lactic Acid / administration & dosage*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nanoparticles
  • Polyglycolic Acid / administration & dosage*
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Receptors, Tumor Necrosis Factor, Member 14 / administration & dosage*


  • Biocompatible Materials
  • Receptors, Tumor Necrosis Factor, Member 14
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid