ACUTE CEREBRAL TOXOPLASMOSIS IS INDUCED BY IN-VIVO NEUTRALIZATION OF TNF-ALPHA AND CORRELATES WITH THE DOWN-REGULATED EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE AND OTHER MARKERS OF MACROPHAGE ACTIVATION

C57BL/6 mice infected with the ME-49 strain of Toxoplasma gondii devel op a progressive encephalitis culminating in 100% mortality between 12 and 15 wk after intraperitoneal inoculation of the parasite. Moreover , when injected at 4 wk after infection with anti-IFN-gamma mAb, progr ession of toxoplasmic encephalitis is markedly accelerated, resulting in death of the animals by 9 to 12 days posttreatment. In this study, we investigated the expression of mRNAs encoding cytokines as well as lymphocyte and macrophage markers during the development of toxoplasmi c encephalitis. High levels of lymphocyte CD4 and CD8 surface Ag trans cript were detected in the brains of mice throughout the infection. In addition from 2 to 4 wk we found elevations of Th1 (IFN-gamma and IL- 2) but not of Th2 (IL-4 and IL-5) cytokine mRNAs. The elevation in Th1 cytokines was accompanied by increases in the expression of monokine (IL-1, IL-6, IL-10, granulocyte macrophage-colony stimulating factor [ GM-CSF], and TNF-alpha) mRNAs, as well as markers expressed by activat ed macrophages (major histocmpatibility class II [Ia], inducible nitri c oxide synthase [iNOS] and macrophage activation gene 1 [Mag-1]). Int erestingly, after 8 wk of infection with T. gondii we observed a drama tic decrease of Th1 cytokine and most monokine (IL-1, IL-6, GM-CSF, an d TNF-alpha) as well as Mag-1 and iNOS mRNA levels. This down-regulati on was associated with enhanced necrosis and neutrophilic infiltrates in the brain accompanied by increased expression of genes expressed sp ecifically by the tachyzoite stage of T. gondii (T. gondii surface ant igen 1 [SAG-1] and T. gondii surface antigen 2 [SAG-2]). Similarly, in mice chronically infected with T gondii and treated with anti-IFN-gam ma mAb the resulting pathology was associated with decreased expressio n of TNF-alpha and iNOS and increased expression of SAG-1 and SAG-2. M oreover, treatment with anti-TNF-alpha mAb also resulted in enhanced p athology, which correlated with low levels of iNOS mRNA and high level s of tachyzoite-specific mRNAs. Together these results suggest that re activation of T. gondii results from a down-regulation of IFN-gamma an d TNF-alpha expression leading to decreased macrophage or microglial c ell activation, release of parasite growth, and subsequent tissue dama ge.