Immunohistochemical identification of trigeminal ganglion neurons that innervate the mouse cornea: Relevance to intercellular spread of herpes simplex virus

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Abstract
Inoculation of the scarified cornea with herpes simplex virus (type 1) leads to herpetic infection of trigeminal ganglion cells. A recent study of the susceptibility of ganglion cells revealed that there may be at least four populations of trigeminal ganglion cells that are infectable by herpes. Two classes were identified by their neuropeptide content: Substance P or calcitonin gene-related peptide. One class was identified by its affinity for a monoclonal antibody, SSEA-3. The fourth class was recognized by its common affinity for both the monoclonal antibody LD2 and for the lectin Bandeiraea simplicifolia isolectin. However, there has been no direct evidence of which types are infected directly as a result of retrograde transport from the corneal site and which may be infected by cell-to-cell spread. The aim of this study was to determine which classes of neurons, which are known to become infected with HSV after ocular inoculation, supply corneal innervation. We have identified four classes of trigeminal ganglion neurons that supply axons to the central cornea of the mouse, on the basis of their ability to transport Fluoro-Gold retrograde from axons in the central corneal epithelium and stroma. About 40% of the neurons that innervate the cornea contain Substance P or calcitonin gene-related peptide; about 60% of the neurons that innervate the cornea react with the monoclonal antibody SSEA-3. About 36% of all neurons in the whole ophthalmic division react with the LD2 or Bandeiraea simplicifolia isolectin, and Fluoro-Gold labels only 2% of them. Thus, the population of LD2/Bandeiraea Simplicifolia Isolectin neurons that innervates the cornea represents less than 1% of the total neurons in the ophthalmic division, although it constitutes about 20% of the infected cells in that division at three days after viral inoculation. We conclude that most of the LD2/Bandeiraea simplicifolia isolectin-positive ganglion cells that are infected with herpes at 3 days are infected as a result of HSV spread from nearby cells in the ganglion or proximal trigeminal root. Neurons labeled with antibodies to Substance P, calcitonin gene-related peptide, or α-SSEA-3 that are primarily infected may be sources of the cell-to-cell spread of virus.