MICE DEFECTIVE IN FAS ARE HIGHLY SUSCEPTIBLE TO LEISHMANIA-MAJOR INFECTION DESPITE ELEVATED IL-12 SYNTHESIS, STRONG TH1 RESPONSES, AND ENHANCED NITRIC-OXIDE PRODUCTION

MRL/MP-lpr/lpr (MRL/lpr) mice have a single mutation (lpr) of the fas apoptosis gene. The mutant mice developed significantly smaller lesion s than the wild-type mice at the earlier stage of infection with the i ntracellular protozoan parasite Leishmania major. However, while all t he wild-type mice achieved complete lesion resolution, the disease in the mutant mice progressed inexorably. The mutant mice had more IL-12 and nitrite/nitrate in the serum than wild-type mice following infecti on. Lymphoid cells from infected MRL/lpr mice produced more IFN-gamma but less IL-4 and IL-5 than cells from MRL-+/+ mice. Peritoneal macrop hages from the mutant mice also produced more IL-12 and NO after stimu lation with LPS. Thus, Fas expression is essential for resistance agai nst leishmaniasis, and Fas-mediated apoptosis may form an integral par t of the Th1-mediated microbicidal function.