The role of perforin and chemokines in the pathogenesis of chronic corneal inflammation induced by herpes simplex virus type-1 infection

Herpes simplex virus type-1 (HSV-1) is the cause of herpetic stromal keratitis (HSK), a significant cause of blindness. T cells are indispensable to the pathogenesis of HSK. We studied the pathogenic role of T cell mediated cytotoxic pathways in HSK. Perforin-deficient (PKO) mice, but not gld mice, developed markedly less corneal inflammation than wildtype (WT) mice following intracorneal inoculation with HSV-1. Adoptive transfer of HSV-1 immune cells from wildtype donors restored corneal inflammation to HSV-1 infected PKO mice. Virus replication was not impaired in the PKO mice. We hypothesized that the reduced severity of HSK in PKO mice was due to modulation of the level of cytokines and/or chemokines in the corneas of PKO mice following infection. We measured the level of expression of a selected group of cytokines and chemokines (which are thought to be important in HSK and other inflammatory diseases) in the corneas of PKO and WT mice following infection. We found that the mRNA and protein levels of MIP-1α, MIP-2 and IL-6 were reduced in the corneas of PKO mice. There were no detectable differences between the two groups in the expression of the other cytokines and chemokines that were examined. The in vivo administration of MIP-1α or MIP-2 significantly increased the severity of the clinical and histological lesions of HSK in HSV-1 infected PKO mice by 23 days post infection. Injection of IL-6 did not significantly increase the severity of HSK. In the absence of CXCR2, the receptor for MIP-2, neutrophil recruitment to the cornea following HSV-1 infection was reduced. Furthermore, CXCR2-deficient mice developed less severe HSK. In conclusion, it appears that MIP-1α and MIP-2 may play a role in the progression of herpes simplex virus induced corneal inflammation following an initiation event which is mediated by perforin, whereas IL-6 may play a less significant role in this process.