Unraveling The Paradoxical Impacts Of Toxoplasma Gondii On Dendritic Cell Stat1 Signaling
Toxoplasma gondii is a protozoan parasite of wide geographic and host range. Although many infections in humans are asymptomatic, the potential exists for severe disease. The parasite is highly successful given its ability to establish life -long infections. To achieve this, the parasite must establish a delicate balance between activation and suppression of the host immune response. The cytokine IFN[gamma] is essential for host resistance to the parasite . Therefore, Toxoplasma actively manipulates the IFN[gamma] pathway in order to ensure parasite survival. It has become clear that Toxoplasma can evade the host IFN[gamma] response in a variety of cell types. However, the exact mechanism by which this occurs remains unclear. Furthermore, evasion of the IFN[gamma] response has not been studied in the dendritic cell, an immune cell type important during in vivo infection. I show that Toxoplasma can block STAT1 binding to IFN[gamma]-responsive gene promoters in dendritic cells, preventing transcription. However, STAT1 activation is not impaired. In fact, I show that Toxoplasma alone causes STAT1 phosphorylation and nuclear translocation, as well as consensus sequence binding. Phosphorylation and consensus sequence binding occur synergistically with IFN[gamma]. However, the parasite induces formation of aberrant STAT1 DNA-binding complexes. Further work shows that Toxoplasma-induced STAT1 phosphorylation and/or synergy with IFN[gamma] occur independently of the parasite kinases ROP16, ROP18, ROP21 as well as the parasitetriggered host MyD88-, GiPCR-, and PI3K-dependent signaling pathways. Furthermore, inhibition of STAT1 transcriptional activity occurs in a parasite strain-independent manner. Synergistic levels of phospho-STAT1 correlate with parasite mediated inhibition of IFN[gamma] induced Socs1 expression. Yet, the parasite alone induces modest Socs1 expression in a ROP16dependent manner, which may participate in regulation of other pathways such as TLR signaling. From this work it is clear that the impacts of Toxoplasma on dendritic cell STAT1 signaling are complex. The parasite induces STAT1 phosphorylatio n, but how this occurs and whether this STAT1 participates in the transcription of a unique subset of genes remains to be determined. However, it is clear that the parasite can block STAT1 chromatin binding and transcription in dendritic cells in response to IFN[gamma], permitting evasion of this important host immune response.
toxoplasma; dendritic cell; stat1
Denkers, Eric Young
Holowka, David Allan; Parker, John Stuart Leslie; Simpson, Kenneth William
Ph.D. of Veterinary Medicine
Doctor of Philosophy
dissertation or thesis