title: Listeria monocytogenes infection in macrophages induces vacuolar-dependent host miRNA response.
abstract: Listeria monocytogenes is a gram-positive facultative intracellular pathogen, causing serious illness in immunocompromised individuals and pregnant women. Upon detection by macrophages, which are key players of the innate immune response against infection, L. monocytogenes induces specific host cell responses which need to be tightly controlled at transcriptional and post-transcriptional levels. Here, we ask whether and how host miRNAs, which represent an important mechanism of post-transcriptional regulation in a wide array of biological processes, are altered by a model pathogen upon live infection of murine bone marrow derived macrophages. We first report that L. monocytogenes subverts the host genome-wide miRNA profile of macrophages in vitro. Specifically, we show that miR-155, miR-146a, miR-125a-3p/5p and miR-149 were amongst the most significantly regulated miRNAs in infected macrophages. Strikingly, these miRNAs were highly upregulated upon infection with the Listeriolysin-deficient L. monocytogenes mutant Δhly, that cannot escape from the phagosome thus representing a vacuolar-contained infection. The vacuolar miRNA response was significantly reduced in macrophages deficient for MyD88. In addition, miR-146a and miR-125a-3p/5p were regulated at transcriptional levels upon infection, and miR-125a-3p/5p were found to be TLR2 responsive. Furthermore, miR-155 transactivation in infection was regulated by NF-κB p65, while miR-146a and miR-125a-3p/5p expression was unaffected in p65-deficient primary macrophages upon L. monocytogenes infection. Our results demonstrate that L. monocytogenes promotes significant changes in the miRNA expression profile in macrophages, and reveal a vacuolar-dependent miRNA signature, listeriolysin-independent and MyD88-dependent. These miRNAs are predicted to target immune genes and are therefore most likely involved in regulation of the macrophage innate immune response against infection at post-transcriptional levels.
authors: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
authors: Anna K D
authors: AK
authors: Schnitger
authors: Alzbeta
authors: A
authors: Machova
authors: Roman Ulrich
authors: RU
authors: Mueller
authors: Ariadne
authors: A
authors: Androulidaki
authors: Bernhard
authors: B
authors: Schermer
authors: Manolis
authors: M
authors: Pasparakis
authors: Martin
authors: M
authors: Krönke
authors: Nikoletta
authors: N
authors: Papadopoulou
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D004269:DNA, Bacterial / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000494:pharmacology; D006460:Hemolysin Proteins / Q000494:pharmacology; D007113:Immunity, Innate; D008089:Listeria monocytogenes / Q000235:genetics / Q000472:pathogenicity*; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000382:microbiology*; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D051195:Toll-Like Receptor 2; D015533:Transcriptional Activation; D014617:Vacuoles / Q000235:genetics / Q000276:immunology* / Q000382:microbiology
chemical_list: D001427:Bacterial Toxins; D004269:DNA, Bacterial; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D035683:MicroRNAs; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C038705:hlyA protein, Listeria monocytogenes