title: A transcriptomic network identified in uninfected macrophages responding to inflammation controls intracellular pathogen survival.
abstract: Intracellular pathogens modulate host cell function to promote their survival. However, in vitro infection studies do not account for the impact of host-derived inflammatory signals. Examining the response of liver-resident macrophages (Kupffer cells) in mice infected with the parasite Leishmania donovani, we identified a transcriptomic network operating in uninfected Kupffer cells exposed to inflammation but absent from Kupffer cells from the same animal that contained intracellular Leishmania. To test the hypothesis that regulated expression of genes within this transcriptomic network might impact parasite survival, we pharmacologically perturbed the activity of retinoid X receptor alpha (RXRα), a key hub within this network, and showed that this intervention enhanced the innate resistance of Kupffer cells to Leishmania infection. Our results illustrate a broadly applicable strategy for understanding the host response to infection in vivo and identify Rxra as the hub of a gene network controlling antileishmanial resistance.
authors.affiliation: Centre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, York YO10 5DD, UK.
authors.forename: Lynette
authors.initials: L
authors.lastname: Beattie
authors.forename: Micely
authors.initials: M
authors.lastname: d'El-Rei Hermida
authors.forename: John W J
authors.initials: JW
authors.lastname: Moore
authors.forename: Asher
authors.initials: A
authors.lastname: Maroof
authors.forename: Najmeeyah
authors.initials: N
authors.lastname: Brown
authors.forename: Dimitris
authors.initials: D
authors.lastname: Lagos
authors.forename: Paul M
authors.initials: PM
authors.lastname: Kaye
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D053263:Gene Regulatory Networks; D054884:Host-Pathogen Interactions; D007249:Inflammation / Q000276:immunology*; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000469:parasitology; D008099:Liver / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology*; D051379:Mice; D059467:Transcriptome
chemical_list: D004268:DNA-Binding Proteins; C061606:Rxrb protein, mouse
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