Trypanosoma cruzi evades the protective role of interferon-gamma-signaling in parasite-infected cells.

Abstract

The protozoan parasite Trypanosoma cruzi is responsible for the zoonotic Chagas disease, a chronic and systemic infection in humans and warm-blooded animals 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 STAT1 and its increased DNA binding. Furthermore, we found that in response to T. cruzi the total amount of intracellular STAT1 increased in an infectious dose-dependent manner, both at the mRNA and protein level. While STAT1 activation is a potent strategy of the host in the fight against the invading pathogen, amastigotes replicating intracellularly antagonize this pathway by specifically promoting the dephosphorylation of STAT1 serine 727, thereby partially circumventing its protective effects. These findings point to the crucial role of the IFNγ/STAT1 signal pathway in the evolutionary combat between T. cruzi parasites and their host.

• Authors: Philipp Stahl, Volker Ruppert, Ralph T Schwarz, Thomas Meyer
• Journal: PloS one (PLoS One) Vol. 9 Issue 10 Pg. e110512 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25340519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• STAT1 Transcription Factor
• STAT1 protein, human
• Phosphoserine
• Interferon-gamma

Topics

• Animals
• Cell Line
• Chagas Disease (genetics, immunology, parasitology)
• Gene Expression Regulation
• Humans
• Immune Evasion
• Interferon-gamma (metabolism)
• Models, Biological
• Parasites (immunology)
• Phosphorylation
• Phosphoserine (metabolism)
• STAT1 Transcription Factor (deficiency, metabolism)
• Signal Transduction
• Trypanosoma cruzi (immunology)