MECHANISMS FOR VIRUS-INDUCED LIVER-DISEASE - TUMOR NECROSIS FACTOR-MEDIATED PATHOLOGY INDEPENDENT OF NATURAL-KILLER AND T-CELLS DURING MURINE CYTOMEGALOVIRUS-INFECTION

The contribution of endogenous NK cells and cytokines to virus-induced liver pathology was evaluated during murine cytomegalovirus infection s of mice. In immunocompetent C57BL/6 mice, the virus induced a self-l imited liver disease characterized by hepatitis, with focal inflammati on, and large grossly visible subcapsular necrotic foci. The inflammat ory foci were most numerous and contained the greatest number of cells 3 days after infection; they colocalized with areas of viral antigen expression. The largest number of necrotic foci was found 2 days after infection. Overall hepatic damage, assessed as increased expression o f liver enzymes in serum, accompanied the development of inflammatory and necrotic foci. Experiments with neutralizing antibodies demonstrat ed that although virus-induced tumor necrosis factor (TNF) can have an tiviral effects, it also mediated significant liver pathology. TNF was required for development of hepatic necrotic foci and increased level s of liver enzymes in serum but not for increased numbers of inflammat ory foci. The necrotic foci and liver enzyme indications of pathology occurred independently of NK and T cells, because mice rendered NK-cel l deficient by treatment with antibodies, T-and B-cell-deficient Rag(- /-) mice, and NK-and T-cell-deficient E26 mice all manifested both par ameters of disease. Development of necrotic foci and maximally increas ed levels of liver enzymes in serum also were TNF dependent in NK-cell -deficient mice. Moreover, in the immunodeficient E26 mice, virus-indu ced liver disease was progressive, with eventual death of the host, an d neutralization of TNF significantly increased longevity. These resul ts establish conditions separating hepatitis from significant liver da mage and demonstrate a cytokine mediated component to viral pathogenes is.