title: Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection.
abstract: Increasing evidence suggests an important role for miRNAs in the molecular interplay between bacterial pathogens and host cells. Here we perform a fluorescence microscopy-based screen using a library of miRNA mimics and demonstrate that miRNAs modulate Salmonella infection. Several members of the miR-15 miRNA family were among the 17 miRNAs that more efficiently inhibit Salmonella infection. We discovered that these miRNAs are downregulated during Salmonella infection, through the inhibition of the transcription factor E2F1. Analysis of miR-15 family targets revealed that derepression of cyclin D1 and the consequent promotion of G1/S transition are crucial for Salmonella intracellular proliferation. In addition, Salmonella induces G2/M cell cycle arrest in infected cells, further promoting its replication. Overall, these findings uncover a mechanism whereby Salmonella renders host cells more susceptible to infection by controlling cell cycle progression through the active modulation of host cell miRNAs.
authors.affiliation: Institute for Molecular Infection Biology (IMIB), University of Würzburg, Josef-Schneider-Strasse 2/D15, 97080 Würzburg, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Maudet
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, Trieste 34149, Italy.
authors.forename: Miguel
authors.initials: M
authors.lastname: Mano
authors.affiliation: Institute for Molecular Infection Biology (IMIB), University of Würzburg, Josef-Schneider-Strasse 2/D15, 97080 Würzburg, Germany.
authors.forename: Ushasree
authors.initials: U
authors.lastname: Sunkavalli
authors.affiliation: Institute for Molecular Infection Biology (IMIB), University of Würzburg, Josef-Schneider-Strasse 2/D15, 97080 Würzburg, Germany.
authors.forename: Malvika
authors.initials: M
authors.lastname: Sharan
authors.affiliation: International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, Trieste 34149, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giacca
authors.affiliation: Institute for Molecular Infection Biology (IMIB), University of Würzburg, Josef-Schneider-Strasse 2/D15, 97080 Würzburg, Germany.
authors.forename: Konrad U
authors.initials: KU
authors.lastname: Förstner
authors.affiliation: Institute for Molecular Infection Biology (IMIB), University of Würzburg, Josef-Schneider-Strasse 2/D15, 97080 Würzburg, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Eulalio
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D019938:Cyclin D1 / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000235:genetics; D005786:Gene Expression Regulation; D006367:HeLa Cells / Q000187:drug effects / Q000382:microbiology; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D000067996:RAW 264.7 Cells / Q000382:microbiology; D012480:Salmonella Infections / Q000235:genetics*; D012486:Salmonella typhimurium / Q000235:genetics / Q000472:pathogenicity
chemical_list: C530104:CCND1 protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D008070:Lipopolysaccharides; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; D019938:Cyclin D1