Murine model of drug-induced reactivation of Toxoplasma gondii

Abstract

A murine model of recrudescence of chronic toxoplasmosis, mimicking this life-threatening condition in immunosuppressed humans, was developed in Swiss-Webster mice infected 6 weeks previously with 10 cysts of the Me49 strain of Toxoplasma gondii, by treatment with dexamethasone (DXM, 2.5 mg/kgBM/day in drinking water), alone or combined with cortisone-acetate (CA, 50 mg/kg by subcutaneous injection 3 times a week). Treatment was continued for 7 weeks. Both DXM and DXM+CA treatment significantly increased mortality, as compared to infected untreated mice (P=0.0002 and P lt 10(-4), respectively), and to uninfected DXM-treated mice (P=0.043 and P=0.001, respectively). In both treatment groups, mean cyst numbers were 2-9-fold increased compared with chronically infected untreated mice. Spleen/body mass ratios and numbers of splenocytes were significantly lower (P lt 10(-4)) than in untreated both infected and uninfected mice, indicating decreased immune reactivity in treated animals. Acquired immunity too was impaired by corticoids, as shown by lower resistance to challenge infection with the mouse-virulent RH strain of T. gondii in mice with established chronic infection treated with DXM than in those left untreated (P=0.038). Most importantly, 8 of the 56 treated animals (14.2%) developed clinical signs of toxoplasmic encephalitis, which was verified histologically. In these, survival was significantly shorter (P=0.009) and cyst numbers 6-fold augmented (P lt 10(-4)) as compared to treated animals, which did not develop neurological signs. This simple model of drug-induced recrudescence of chronic toxoplasmosis, in addition to its potential use for in vivo studies of the pathogenic mechanisms of T. gondii reactivation, may be particularly suitable for the evaluation of chemotherapeutics.