Trypanosoma cruzi Evades the Protective Role of Interferon-Gamma-Signaling in Parasite-Infected Cells

The protozoan parasite Trypanosoma cruziis responsible for the zoonotic Chagas disease, a chronic and systemic infection in humans and warm-bloodedanimals typically leading to progressive dilated cardiomyopathy and gastrointestinal manifestations. In the present study, we report that the transcription factor STAT1(signal transducer and activator of transcription 1) reduces the susceptibility of human cells to infection with T. cruzi. Our in vitro data demonstrate that interferon -γ (IFNγ) pre-treatment causes T. cruzi-infected cells to enter an anti-parasitic state through the activation of the transcription factor STAT1. Whereas stimulation of STAT1-expressing cells with IFNγ significantly impaired intracellular replication of parasites, no protective effect of IFNγ was observed in STAT1-deficient U3A cells. The gene encoding indoleamine 2, 3- dioxygenase(ido) was identified as a STAT1-regulated target gene engaged in parasite clearance. Exposure of cells to T. cruzi trypomastigotes in the absence of IFNγ resulted in both sustained tyrosine and serine phosphorylation of STAT1and its increased DNA binding. Furthermore, we found that in response to T. cruzi the total amount of intracellular STAT1increased in an infectious dose-dependent manner, both at the mRNA and protein level. While STAT1activation is a potent strategy of the host in the fight against the invading pathogen, amastigotesreplicating intracellularly antagonize this pathway by specifically promoting the dephosphorylation of STAT1serine 727, thereby partially circumventing its protective effects. These findings point to the crucial role of the IFNγ/ STAT1signal pathway in the evolutionary combat between T. cruzi parasites and their host.