Purpose  Patients with herpes simplex keratitis (HSK) demonstrate decreased corneal nerve density within days of infection, resulting in loss of sensation. During HSK, herpes simplex virus (HSV)-1spreads to the trigeminal ganglion (TG) through retrograde travel in corneal nerves. To date, little is known about the early pathogenesis of host-pathogen interaction in HSK. The purpose of this study was to investigate early nerve destruction, as well as related immune responses in HSK.
Methods  C57BL/6mice were infected by ocular inoculation with HSV-1 McKrae, while control mice were inoculated with virus medium. Corneas were excised at days 1, 2, and 3 after inoculationand immunofluorescence staining with antibodies against HSV-1, β-Tubulin, CD11c, CD11b, MHC-II was performed by confocal microscopy on whole-mounted corneas.
Results  As early as 24 h post infection (PI), initial focal destruction of the subbasal nerves was noted below infected epithelial cells. On day 3 PI, the subbasal nerve plexus was completely destroyed in the infected areas with only few nerves left. The central subbasal nerve density on day 1, 2 and 3 PI were 64000±8970µm/mm², 14800±3400µm/mm² and 1450±530µm/mm² respectively, which was significantlydecreased as compared to control mice (124500±46370µm/mm²)(p<0.01, p<0.0001, p<0.0001). On day 1 PI, corneal nerves started to get infected by HSV-1. Interestingly, all infected nerves were located peripherally. Concomitant with nerve destruction, there was a significant increase in CD11c⁺ and CD11b⁺ cells both in the central (167±35 cells/mm², 413±65 cells/mm²) and peripheral (467±81 cells/mm², 873±95 cells/mm²) cornea, as compared to central (67±11cells/mm², 247±72cells/mm²) (p<0.001, p<0.05) and peripheral (207±23cells/mm², 280±87cells/mm²) (p<0.01, p<0.001) normal corneas. Moreover, there was a significant increase in MHC-II expression on CD11c⁺ cells (p<0.01) throughout the cornea.
Conclusions  Subbasal cornea nerves are destroyed extensively, immediately after infection with HSV-1. HSV-1 can only be observed in peripheral corneal nerves from day 1 PI, but not centrally. The destruction of corneal nerves is accompanied with the significant increase and maturation of corneal antigen-presenting cells.