A Gain-of-Function Genomic Screen Identifies the Orphan Nuclear Receptor TLX as an Enhancer of STAT1-mediated Transcription and Immunity to Toxoplasma gondii: TLX overexpression
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ABSTRACT: The protozoan parasite Toxoplasma gondii is a highly successful intracellular pathogen, owing in part to its ability to subvert the host immune system. In particular, parasite infection suppresses STAT1 signaling in a variety of cell types, including IFN-γ activated macrophages, via a block within the nucleus. A high-throughput screen to identify genes able to overcome parasite-mediated suppression of STAT1 activity identified 9 transcription factors as enhancers of STAT1 signaling in T. gondii infected cells, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that TLX is a transcriptional regulator that drives the steady-state expression of STAT1-independent genes involved brain function and development, while enhancing the output of a subset of IFN-γ-dependent target genes. Infection of TLX deficient mice with Toxoplasma results in impaired production of interleukin-12 by dendritic cells and increased parasite burden in the brain during chronic infection. These results demonstrate a previously unrecognized function 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’.
ORGANISM(S): Homo sapiens
PROVIDER: GSE55749 | GEO | 2015/05/29
SECONDARY ACCESSION(S): PRJNA240890
REPOSITORIES: GEO
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