A MicroRNA Network Controls Legionella pneumophila Replication in Human Macrophages via LGALS8 and MX1
| Autor: | Brian E. Caffrey, C Herkt, Leon N. Schulte, Annalisa Marsico, Bernd Schmeck, Kerstin Hoffmann, Wei Chen, Uwe Völker, Wilhelm Bertrams, Stefanie M. Herbel, Sascha Blankenburg, Alexandra Sittka-Stark, Manuela Gesell Salazar, Kristin Surmann, Anna L. Jung, Martin Vingron |
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| Rok vydání: | 2020 |
| Předmět: |
Myxovirus Resistance Proteins
Proteome THP-1 Cells Virulence Factors Legionella infectious disease Galectins macrophage Microbiology Legionella pneumophila Host-Microbe Biology RIG-I 03 medical and health sciences 0302 clinical medicine galectin-8 Virology microRNA Gene expression Humans MX1 TP53 bacteria DDX58 miRNA 030304 developmental biology 0303 health sciences biology Effector Macrophages biology.organism_classification infection QR1-502 respiratory tract diseases Chromatin Cell biology MicroRNAs Gene Expression Regulation Mirna Infection Macrophage Mx1 Bacteria Galectin-8 inflammation 030220 oncology & carcinogenesis Host-Pathogen Interactions Legionnaires' Disease Chromatin immunoprecipitation Research Article Signal Transduction |
| Zdroj: | mBio 11:e03155-19 (2020) mBio, Vol 11, Iss 2 (2020) mBio mBio, Vol 11, Iss 2, p e03155-19 (2020) |
| ISSN: | 2150-7511 2161-2129 |
| DOI: | 10.1128/mbio.03155-19 |
| Popis: | Cases of Legionella pneumophila pneumonia occur worldwide, with potentially fatal outcome. When causing human disease, Legionella injects a plethora of virulence factors to reprogram macrophages to circumvent immune defense and create a replication niche. By analyzing Legionella-induced changes in miRNA expression and genomewide chromatin modifications in primary human macrophages, we identified a cell-autonomous immune network restricting Legionella growth. This network comprises three miRNAs governing expression of the cytosolic RNA receptor DDX58/RIG-I, the tumor suppressor TP53, the antibacterial effector LGALS8, and MX1, which has been described as an antiviral factor. Our findings for the first time link TP53, LGALS8, DDX58, and MX1 in one miRNA-regulated network and integrate them into a functional node in the defense against L. pneumophila. Legionella pneumophila is an important cause of pneumonia. It invades alveolar macrophages and manipulates the immune response by interfering with signaling pathways and gene transcription to support its own replication. MicroRNAs (miRNAs) are critical posttranscriptional regulators of gene expression and are involved in defense against bacterial infections. Several pathogens have been shown to exploit the host miRNA machinery to their advantage. We therefore hypothesize that macrophage miRNAs exert positive or negative control over Legionella intracellular replication. We found significant regulation of 85 miRNAs in human macrophages upon L. pneumophila infection. Chromatin immunoprecipitation and sequencing revealed concordant changes of histone acetylation at the putative promoters. Interestingly, a trio of miRNAs (miR-125b, miR-221, and miR-579) was found to significantly affect intracellular L. pneumophila replication in a cooperative manner. Using proteome-analysis, we pinpointed this effect to a concerted downregulation of galectin-8 (LGALS8), DExD/H-box helicase 58 (DDX58), tumor protein P53 (TP53), and then MX dynamin-like GTPase 1 (MX1) by the three miRNAs. In summary, our results demonstrate a new miRNA-controlled immune network restricting Legionella replication in human macrophages. |
| Databáze: | OpenAIRE |
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