title: Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells.
abstract: Antiviral mechanisms by which natural killer (NK) cells control murine cytomegalovirus (MCMV) infection in the spleens and livers of C57BL/6 mice were measured, revealing different mechanisms of control in different 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 depletion in MCMV-infected perforin 0/0 mice resulted only in an increase in liver viral titers and not in spleen titers. Depletion of gamma interferon (IFN-gamma) in C57BL/6 mice by injections with monoclonal antibodies to IFN-gamma resulted in an increase of viral titers in the liver but not in the spleen. Analyses using IFN-gamma-receptor-deficient mice, rendered chimeric with C57BL/6 bone marrow cells, indicated that in a recipient environment where IFN-gamma cannot exert its effects, 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 administrating the nitric oxide synthase inhibitor N(omega)-monomethyl-L-arginine into 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-lr locus, which maps closely to genes regulating NK cell cytotoxic function, confers an NK cell-dependent resistance to MCMV infection in the spleen but not in the liver.
authors.affiliation: Department of Pathology, University of Massachusetts Medical Center, Worcester 01655, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Tay
authors.forename: R M
authors.initials: RM
authors.lastname: Welsh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D005260:Female; D017353:Gene Deletion; D007371:Interferon-gamma / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000821:virology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000254:growth & development / Q000276:immunology* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000821:virology; D014407:Tumor Cells, Cultured; D014779:Virus Replication; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D017471:Receptors, Interferon; D054353:Perforin; D019323:omega-N-Methylarginine; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase