title: The Orphan Nuclear Receptor TLX Is an Enhancer of STAT1-Mediated Transcription and Immunity to Toxoplasma gondii.
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."
authors.affiliation: Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, Philadelphia, United States of America.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Beiting
authors.affiliation: Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, Philadelphia, United States of America.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hidano
authors.affiliation: Department of Pharmacology and the Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Baggs
authors.affiliation: Department of Pharmacology and the Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Geskes
authors.affiliation: Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, Philadelphia, United States of America.
authors.forename: Qun
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.affiliation: Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, Philadelphia, United States of America.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: David S
authors.initials: DS
authors.lastname: Roos
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Cherry
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002494:Central Nervous System Infections / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D002908:Chronic Disease; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D007371:Interferon-gamma / Q000378:metabolism; D008808:Mice, Inbred CBA; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D014122:Toxoplasma / Q000276:immunology*
chemical_list: D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; C490258:Nr2e1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma