Absence of macrophage inflammatory protein-1α prevents the development of blinding herpes stromal keratitis

Prior studies in our laboratory have suggested that the CC chemokine macrophage inflammatory protein-1 alpha (MIP-1 alpha) may be an important mediator in the blinding ocular inflammation which develops following herpes simplex virus type 1 (HSV-1) infection of the murine cornea. To directly test this hypothesis, MIP-1 alpha-deficient (-/-) mice and their wild-type (+/+) counterparts were infected topically on the scarified cornea with 2.5 x 10(5) PFU of HSV-1 strain RE and subsequently graded for corneal opacity, Four weeks postinfection (p.i.), the mean corneal opacity score of -/- mice was 1.1 +/- 0.3 while that of the +/+ mice was 3.7 +/- 0.5. No detectable infiltrating CD4(+) T cells were seen histologically at 14 or 21 days p.i. in -/- animals, whereas the mean CD4(+) T-cell count per field (36 fields counted) in +/+ hosts was 26 +/- 2 (P < 0.001). In addition, neutrophil counts in the -/- mouse corneas were reduced by > 80% in comparison to the wild-type controls. At 2 weeks p.i., no interleukin-2 or gamma interferon could be detected in six of seven -/- mice, whereas both T-cell cytokines were readily demonstrable in +/+ mouse corneas, Also, MIP-2 and monocyte chemoattractant protein-1 protein levels were significantly lower in MIP-1 alpha -/- mouse corneas than in +/+ host corneas, suggesting that MIP-1 alpha directly, or more likely indirectly, influences the expression of other chemokines. Interestingly, despite the paucity of infiltrating cells, HSV-1 clearance from the eyes of -/- mice was not significantly different from that observed in +/+ hosts. We conclude that MIP-1 alpha is not needed to control virus growth in the cornea but is essential for the development of severe stromal keratitis.