title: Degeneration and regeneration of corneal nerves in response to HSV-1 infection.
abstract: OBJECTIVE
  Herpes simplex virus type 1 (HSV-1) infection is one cause of neurotrophic keratitis, characterized by decreases in corneal sensation, blink reflex, and tear secretion as consequence of damage to the sensory fibers innervating the cornea. Our aim was to characterize changes in the corneal nerve network and its function in response to HSV-1 infection.
  
  
  METHODS
  C57BL/6J mice were infected with HSV-1 or left uninfected. Corneas were harvested at predetermined times post infection (pi) and assessed for β III tubulin, substance P, calcitonin gene-related peptide, and neurofilament H staining by immunohistochemistry (IHC). Corneal sensitivity was evaluated using a Cochet-Bonnet esthesiometer. Expression of genes associated with nerve repair was determined in corneas by real time RT-PCR, Western blotting, and IHC. Semaphorin 7A (SEMA 7A) neutralizing antibody or isotype control was subconjunctivally administered to infected mice.
  
  
  RESULTS
  The area of cornea occupied by β III tubulin immunoreactivity and sensitivity significantly decreased by day 8 pi. Modified reinnervation was observed by day 30 pi without recovery of corneal sensation. Sensory fibers were lost by day 8 pi and were still absent or abnormal at day 30 pi. Expression of SEMA 7A increased at day 8 pi, localizing to corneal epithelial cells. Neutralization of SEMA 7A resulted in defective reinnervation and lower corneal sensitivity.
  
  
  CONCLUSIONS
  Corneal sensory nerves were lost, consistent with loss of corneal sensation at day 8 pi. At day 30 pi, the cornea reinnervated but without recovering the normal arrangement of its fibers or function. SEMA 7A expression was increased at day 8pi, likely as part of a nerve regeneration mechanism.
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Chucair-Elliott
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
authors.forename: Daniel J J
authors.initials: DJ
authors.lastname: Carr
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology* / Q000821:virology; D003315:Cornea / Q000294:innervation* / Q000821:virology; D004279:DNA, Viral / Q000032:analysis*; D004195:Disease Models, Animal; D015828:Eye Infections, Viral / Q000473:pathology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics*; D016849:Keratitis, Herpetic / Q000473:pathology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration
chemical_list: D004279:DNA, Viral
keywords: HSV-1; corneal nerves; neurotrophic keratitis; reinnervation; semaphorin 7A