title: Analysis of the host microRNA response to Salmonella uncovers the control of major cytokines by the let-7 family.
abstract: MicroRNAs have well-established roles in eukaryotic host responses to viruses and extracellular bacterial pathogens. In contrast, microRNA responses to invasive bacteria have remained unknown. Here, we report cell type-dependent microRNA regulations upon infection of mammalian cells with the enteroinvasive pathogen, Salmonella Typhimurium. Murine macrophages strongly upregulate NF-κB associated microRNAs; strikingly, these regulations which are induced by bacterial lipopolysaccharide (LPS) occur and persist regardless of successful host invasion and/or replication, or whether an inflammatory response is mounted, suggesting that microRNAs belong to the first line of anti-bacterial defence. However, a suppression of the global immune regulator miR-155 in endotoxin-tolerant macrophages revealed that microRNA responses also depend on the status of infected cells. This study identifies the let-7 family as the common denominator of Salmonella-regulated microRNAs in macrophages and epithelial cells, and suggests that repression of let-7 relieves cytokine IL-6 and IL-10 mRNAs from negative post-transcriptional control. Our results establish a paradigm of microRNA-mediated feed-forward activation of inflammatory factors when mammalian cells are targeted by bacterial pathogens.
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Leon N
authors.initials: LN
authors.lastname: Schulte
authors.forename: Ana
authors.initials: A
authors.lastname: Eulalio
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.forename: Richard
authors.initials: R
authors.lastname: Reinhardt
authors.forename: Jörg
authors.initials: J
authors.lastname: Vogel
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D035683:MicroRNAs; D051197:Toll-Like Receptor 4; C487931:mirnlet7 microRNA, human; C542687:mirnlet7 microRNA, mouse; D016753:Interleukin-10