Herpes keratitis in the absence of anterograde transport of virus from sensory ganglia to the cornea

Herpes stromal keratitis is an immunopathologic disease in the corneal stroma leading to scarring, opacity, and blindness, and it is an important problem in common corneal surgeries. Paradoxically, virus antigens are largely focused in the epithelial layer of the cornea and not in the stromal layer, and viral antigens are eliminated before stromal inflammation develops. It is not clear what drives inflammation, whether viral antigens are necessary, or how viral antigens reach the stroma. It has been proposed that herpes simplex virus (HSV) travels from the corneal epithelium to sensory ganglia then returns to the stroma to cause disease. However, there is also evidence of HSV DNA and infectious virus persistent in corneas, and HSV can be transmitted to transplant recipients. To determine whether HSV resident in the cornea could cause herpes stromal keratitis, we constructed an HSV US9^- mutant that had diminished capacity to move in neuronal axons. US9^- HSV replicated and spread normally in the mouse corneal epithelium and to the trigeminal ganglia. However, US9^- HSV was unable to return from ganglia to the cornea and failed to cause periocular skin disease, which requires zosteriform spread from neurons. Nevertheless, US9^- HSV caused keratitis. Therefore, herpes keratitis can occur without anterograde transport from ganglia to the cornea, probably mediated by virus persistent in the cornea.