EXACERBATED VIRAL-HEPATITIS IN IFN-GAMMA RECEPTOR-DEFICIENT MICE IS NOT SUPPRESSED BY IL-12

Both IL-12 and IFN-gamma have been implicated as principal inducers of type 1 immune responses required for the elimination of intracellular pathogens, such as viruses. We examined the in vivo antiviral role of both cytokines during coronavirus-induced hepatitis in a mouse hepati tis virus (MHV) model. The absence of IFN-gamma function in mice with a targeted disruption of the IFN-gamma R alpha-chain gene (IFN-gamma R -/-) resulted in increased susceptibility to coronaviral hepatitis as sociated with augmented viral replication and increased hepatocellular injury. The mutant mice showed a type 1 lymphokine response character ized by the normal high IFN-gamma and low IL-4 production. Unlike MHV- infected wild-type mice, however, the mutant IFN-gamma R -/- mice show ed no increase in IL-12 p40 gene expression, similar to that in naive animals. IL-12 treatment failed to restore host resistance in IFN-gamm a R -/- mice, but significantly protected MHV-susceptible C57BL/6 mice against lethal infection, although less than IFN-gamma treatment. Mic e protected by IL-12 or IFN-gamma showed resistance against an otherwi se lethal second MHV infection. Our data demonstrate that despite redu ced IL-12 gene expression and defective IFN-gamma R function, virus-in duced IFN-gamma production can occur. Furthermore, they emphasize the pivotal antiviral role of IFN-gamma in protection against acute corona virus-induced hepatitis.