Pathogenesis of herpes simplex virus type 1-induced corneal inflammation in perforin-deficient mice.
Herpetic stromal keratitis (HSK) is an inflammatory disease of the cornea that often results in blindness. It is mediated by a host immune response which is triggered by herpes simplex virus (HSV) infection. Immune effector mechanisms are hypothesized to be important in disease development. We investigated, in a mouse model, whether perforin-dependent cytotoxicity is an important effector mechanism in the production of HSK. Wild-type (C57BL/6) and perforin-deficient (PKO) mice were infected intracorneally with HSV-1 strain F. Clinical disease and histologic lesions of the cornea at 23 days postinfection (p.i.) were significantly less severe in HSV-1-infected PKO mice than in infected wild-type mice. mRNA for the chemokine macrophage inflammatory protein 1alpha (MIP-1alpha) was detected by reverse transcription-PCR in the corneas of infected wild-type mice but not in the corneas of infected PKO mice at 23 days p.i. Adoptive transfer of wild-type HSV-1 immune T-cell-enriched splenocytes into HSV-1-infected PKO mice restored the disease phenotype which was seen in infected wild-type mice. In contrast, mice carrying a null-function mutation in the Fas ligand, which is involved in an alternative cytotoxic mechanism, developed clinical disease and histologic lesions which were comparable to those in wild-type mice. Viral clearance from the eyes of PKO mice was not impaired. There was no significant difference between the infectious viral titers isolated from the eyes of PKO and wild-type mice. Our findings show that perforin is important in the pathogenesis of HSK.
Chang
E
E
Department of Molecular Microbiology-Immunology, School of Medicine, College of Veterinary Medicine, University of Missouri, Columbia, Missouri 65211, USA.
Galle
L
L
Maggs
D
D
Estes
D M
DM
Mitchell
W J
WJ
D000818:Animals; D015967:Gene Expression Regulation, Viral; D018259:Herpesvirus 1, Human; D016849:Keratitis, Herpetic / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin