DECREASED RESISTANCE OF TNF RECEPTOR P55-DEFICIENT AND P75-DEFICIENT MICE TO CHRONIC TOXOPLASMOSIS DESPITE NORMAL ACTIVATION OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN-VIVO

The importance of TNF-alpha in host defense to the intracellular paras ite, Toxoplasma gondii, was investigated in mice lacking both the p55 and p75 receptors for this cytokine. Upon i.p. infection with the avir ulent ME49 strain, knockout mice were capable of limiting acute i.p. i nfection, but succumbed within 3 to 4 wk to a fulminant necrotizing en cephalitis, Receptor deficient mice harbored higher cyst burdens and e xhibited uncontrolled tachyzoite replication in the brain, The luck of TNF receptors did not adversely affect the development of a type 1 IF N-gamma response. In vitro studies with peritoneal macrophages stimula ted with IFN-gamma and tachyzoites indicated that under limiting conce ntrations of IFN-gamma, nitric oxide-mediated toxoplasmastatic activit y is TNF-alpha dependent, However, this requirement is overcome by inc reasing the dose of IFN-gamma, Furthermore, both es vivo and in vivo s tudies demonstrated that inducible nitric oxide synthase induction in the peritoneal cavity and brain is unimpaired in receptor-deficient mi ce, Thus, TNF-dependent immune control of T. gondii expansion in the b rain involves an effector function distinct from inducible nitric oxid e synthase activation.