APOPTOSIS MEDIATED BY FAS BUT NOT TUMOR-NECROSIS-FACTOR RECEPTOR-1 PREVENTS CHRONIC DISEASE IN MICE INFECTED WITH MURINE CYTOMEGALOVIRUS

The role of Fas- and TNF-receptor 1 (TNF-R1)-mediated apoptosis in the clearance of virally infected cells and in the regulation of the immu ne response was analyzed after murine cytomegalovirus (MCMV) infection of C57BL/6 (B6)-+/+ mice, Fas-mutant B6-lpr/lpr mice, TNF-R1 knockout B6-tnfr(0/0) mice, and double-deficient B6-tnfr(0/0) lpr/lpr mice. Th ere was approximately equivalent clearance of MCMV in B6-+/+, B6-tnfr( 0/0), and B6-lpr/lpr mice, and by day 28 no infectious virus could be detected in the liver, kidney, lung, or peritoneal exudate. However, d elayed virus clearance was observed in B6-tnfr(0/0) lpr/lpr mice. An a cute inflammatory response occurred in the liver, lung, and kidney of all mice, which was most severe 7 d after MCMV infection, but resolved by day 28 in B6-+/+ and B6-tnfr(0/0) mice, but not in B6-lpr/lpr or B 6-tnfro'o lpr/lpr mice. These results indicate that apoptosis mediated by either Fas or TNF-R1 is sufficient for rapid clearance of the viru s. However, apoptosis induced by Fas, but not TNF-R1, is required for the downmodulation of the immune response to the virus and prevention of a chronic inflammatory reaction.