PERFORIN-MEDIATED CYTOLYSIS PLAYS A LIMITED ROLE IN HOST-RESISTANCE TO TOXOPLASMA-GONDII

Resistance of perforin knockout (PKO) mice to infection with Toxoplasm a gondii was assessed in models of acute infection and during chronic disease. PKO mice vaccinated with the attenuated mutant, ts-4, display ed severely defective CTL responses against tachyzoite-infected target s. Lysis of the NK target, YAC-1, was also severely impaired in PKO mi ce following ts-4 vaccination. In contrast, wild-type mice developed h igh levels of CTL and NK lytic activity after ts-4 vaccination. Despit e severely defective lytic activity, vaccinated PKO animals were compl etely resistant to challenge with the virulent strain RH, which normal ly causes a lethal acute infection. Resistance was attributable to pro duction of IFN-gamma, which remained unimpaired in the PKO animals. In contrast, when PKO mice were infected with low virulence parasite str ain ME49, which progresses to the cyst-forming stage after passage thr ough an acute phase, accelerated mortality was observed beginning at 7 5 days postinfection. A three- to fourfold increase in brain cyst numb ers was also found by day 30 in infected PKO animals. Nevertheless, th e PKO strain produced normal levels of IFN-gamma after ME49 infection, ruling,out impaired production of the latter cytokine as a cause of i ncreased susceptibility. Together, these results show that perforin-de pendent cytolytic function is not required for host resistance to leth al acute infection in preimmunized animals, but that the latter activi ty contributes to the control of infection during the chronic stage.