Toxoplasma gondii and Schistosoma mansoni synergize to promote hepatocyte dysfunction associated with high levels of plasma TNF-alpha and early deathin C57BL/6 mice

To address the question of how the murine host responds to a prototypic typ e 1 cytokine inducer while concurrently undergoing a helminth-induced type 2 cytokine response, C57BL/6 strain animals with patent schistosomiasis man soni were orally infected with the cystogenic Toxoplasma gondii strain ME49 , Schistosoma mansoni infection resulted in a significantly higher mortalit y rate when mice were subsequently orally infected with ME49, and these ani mals displayed a defective IFN-gamma and NO response relative to animals in fected with T. gondii alone. Plasma levels of TNF-alpha and aspartate trans aminase in double-infected mice were greatly elevated relative to mice infe cted with either parasite alone, Consistent with the latter observation, th ese animals exhibited severe liver pathology, with regions of coagulative n ecrosis and hepatocyte vacuolization unapparent in mice carrying either inf ection alone. Interestingly, mean egg granuloma size was similar to 50% of that in mice with S, mansoni infection alone. The exacerbated liver patholo gy in coinfected mice did not appear to be a result of uncontrolled tachyzo ite replication, because both parasite-specific RT-PCR analysis and immunoh istochemical staining demonstrated a low number of tachyzoites in the liver . We hypothesize that mortality in these animals results from the high leve l of systemic TNF-alpha, which mediates a severe liver pathology culminatin g in death of the animal.