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PLoS Biol. 2015 Jul 21;13(7):e1002200. doi: 10.1371/journal.pbio.1002200. eCollection 2015 Jul.

The Orphan Nuclear Receptor TLX Is an Enhancer of STAT1-Mediated Transcription and Immunity to Toxoplasma gondii.

Author information

1
Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, Philadelphia, United States of America.
2
Department of Pharmacology and the Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
3
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
4
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Abstract

The protozoan parasite, Toxoplasma, like many intracellular pathogens, suppresses interferon gamma (IFN-γ)-induced signal transducer and activator of transcription 1 (STAT1) activity. We exploited this well-defined host-pathogen interaction as the basis for a high-throughput screen, identifying nine transcription factors that enhance STAT1 function in the nucleus, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that upon IFN-γ treatment TLX enhances the output of a subset of IFN-γ target genes, which we found is dependent on TLX binding at those loci. Moreover, infection of TLX deficient mice with the intracellular parasite Toxoplasma results in impaired production of the STAT1-dependent cytokine interleukin-12 by dendritic cells and increased parasite burden in the brain during chronic infection. These results demonstrate a previously unrecognized role for this orphan nuclear hormone receptor in regulating STAT1 signaling and host defense and reveal that STAT1 activity can be modulated in a context-specific manner by such "modifiers."

Comment in

PMID:
26196739
PMCID:
PMC4509904
DOI:
10.1371/journal.pbio.1002200
[Indexed for MEDLINE]
Free PMC Article

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