Toxoplasma gondii down-regulates MHC class II gene expression and antigen presentation by murine macrophages via interference with nuclear translocation of STAT1 alpha

The obligate intracellular protozoan parasite Toxoplasma gondii is able to establish persistent infections within human and animal hosts. We have show n recently that T. gondii downregulates IFN-gamma -induced MHC class II exp ression in murine bone marrow-derived macrophages (BMM phi). As shown in th is study, the capacity of IFN-gamma -activated murine BMM phi to present ov albumin to CD4(+) T cell hybridomas was dose-dependently inhibited by T. go ndii. IFN-gamma -induced up-regulation of H2-Aa, H2-Ab, H2-Eb, H2-Ma, H2-Mb , H2-Oa and invariant chain transcripts was prominently down-regulated by T . gondii. Furthermore, mRNA levels of class II transactivator and interfero n-regulatory factor-1 were significantly diminished. Electromobility shift assays demonstrated a decrease in the binding activity of nuclear extracts to the IFN-gamma -activated site after infection with T gondii, indicating parasitic interference with IFN-gamma -induced signaling. However, neither the expression of the IFN-gammaR nor the IFN-gamma -induced tyrosine phosph orylation of IFN-gammaR alpha chain and signal transducer and activator of transcription (STAT) 1 alpha was diminished by T. gondii. IFN-gamma -induce d nuclear translocation of STAT1 alpha was nevertheless inhibited after inf ection as demonstrated by immunofluorescence microscopy and subcellular fra ctionation analyses. In conclusion, this novel mechanism of microbial inter ference with MHC class II gene expression may contribute to intracellular s urvival and establishment of persistent infection with T:gondii.