Concerted action of the FasL/Fas and perforin/granzyme A and B pathways ismandatory for the development of early viral hepatitis but not for recovery from viral infection

Cytotoxic T lymphocytes (CTL) play a major role in the recovery from primar y viral infections and the accompanying tissue injuries. However, it is unc lear to what extent the two main cytolytic pathways, perforin-granzyme A an d B exocytosis and Fas ligand (FasL)-Fas interaction, contribute to these p rocesses. Here we have employed mouse strains with either spontaneous mutat ions or targeted gene defects in one or more components of either of the tw o cytolytic pathways to analyze the molecular basis of viral clearance and induction of hepatitis during lymphocytic choriomeningitis virus infection. Our results reveal that viral clearance is solely dependent on perforin bu t that virus-induced liver damage only occurs when both the FasL/Fas and th e perforin pathways, including granzymes A and B, are simultaneously activa ted. The finding that development of hepatitis but not viral clearance is d ependent on the concomitant activation of FasL-Fas and perforin-granzymes m ay be helpful in designing novel strategies to prevent hepatic failures dur ing viral infections.