DISTINCT ORGAN-DEPENDENT MECHANISMS FOR THE CONTROL OF MURINE CYTOMEGALOVIRUS-INFECTION BY NATURAL-KILLER-CELLS

Antiviral mechanisms by which natural killer (Mt) cells control murine cytomegalovirus (MCMV) infection in the spleens and livers of C57BL/6 mice were measured, revealing different mechanisms of control in diff erent organs. Three days postinfection, MCMV titers in the spleens of perforin 0/0 mice were higher than in those of perforin +/+ mice, but no elevation of liver titers was found in perforin 0/0 mice, NK cell d epletion in MCMV-infected perforin 0/0 mice resulted only in an increa se in liver viral titers and not in spleen titers. Depletion of gamma interferon (IFN-gamma) in C57BL/6 mice by injections with monoclonal a ntibodies to IFN-gamma resulted in an increase of viral titers in the liver but not in the spleen, Analyses using IFN-gamma-receptor-deficie nt mice, rendered chimeric with C57BL/6 bone marrow cells, indicated t hat in a recipient environment where IFN-gamma cannot exert its effect s, the depletion of NK cells caused an increase in MCMV titers in the spleens but had little effect in the liver. IFN-gamma has the ability to induce a variety of cells to produce nitric oxide, and administrati ng the nitric oxide synthase inhibitor N-omega-monomethyl-L-arginine i nto MCMV-infected C57BL/6 mice resulted in MCMV titer increases in the liver but not in the spleen. Taken together, these data suggest that in C57BL/6 mice, there is a dichotomy in the mechanisms utilized by NK cells in the regulation of MCMV in different organs, In the spleen NK cells exert their effects in a perforin-dependent manner, suggesting a cytotoxic mechanism, while in the liver the production of IFN-gamma by NK cells may be a predominant mechanism in the regulation of; MCMV synthesis. These results may explain why the Cmv-1(r) locus, which map s closely to genes regulating NK cell cytotoxic function, confers an N E cell-dependent resistance to MCMV infection in the spleen but not in the liver.