A MicroRNA Network Controls <italic toggle="yes">Legionella pneumophila</italic> Replication in Human Macrophages via LGALS8 and MX1
ABSTRACT 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...
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American Society for Microbiology
2020
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oai:doaj.org-article:f562f453df8b4591a2a3cac252c1f3ca2021-11-15T15:57:03ZA MicroRNA Network Controls <italic toggle="yes">Legionella pneumophila</italic> Replication in Human Macrophages via LGALS8 and MX110.1128/mBio.03155-192150-7511https://doaj.org/article/f562f453df8b4591a2a3cac252c1f3ca2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03155-19https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.Christina E. HerktBrian E. CaffreyKristin SurmannSascha BlankenburgManuela Gesell SalazarAnna L. JungStefanie M. HerbelKerstin HoffmannLeon N. SchulteWei ChenAlexandra Sittka-StarkUwe VölkerMartin VingronAnnalisa MarsicoWilhelm BertramsBernd SchmeckAmerican Society for MicrobiologyarticlemiRNAinfectionmacrophageMX1bacteriagalectin-8MicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020) |
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miRNA infection macrophage MX1 bacteria galectin-8 Microbiology QR1-502 |
| spellingShingle |
miRNA infection macrophage MX1 bacteria galectin-8 Microbiology QR1-502 Christina E. Herkt Brian E. Caffrey Kristin Surmann Sascha Blankenburg Manuela Gesell Salazar Anna L. Jung Stefanie M. Herbel Kerstin Hoffmann Leon N. Schulte Wei Chen Alexandra Sittka-Stark Uwe Völker Martin Vingron Annalisa Marsico Wilhelm Bertrams Bernd Schmeck A MicroRNA Network Controls <italic toggle="yes">Legionella pneumophila</italic> Replication in Human Macrophages via LGALS8 and MX1 |
| description |
ABSTRACT 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. IMPORTANCE 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. |
| format |
article |
| author |
Christina E. Herkt Brian E. Caffrey Kristin Surmann Sascha Blankenburg Manuela Gesell Salazar Anna L. Jung Stefanie M. Herbel Kerstin Hoffmann Leon N. Schulte Wei Chen Alexandra Sittka-Stark Uwe Völker Martin Vingron Annalisa Marsico Wilhelm Bertrams Bernd Schmeck |
| author_facet |
Christina E. Herkt Brian E. Caffrey Kristin Surmann Sascha Blankenburg Manuela Gesell Salazar Anna L. Jung Stefanie M. Herbel Kerstin Hoffmann Leon N. Schulte Wei Chen Alexandra Sittka-Stark Uwe Völker Martin Vingron Annalisa Marsico Wilhelm Bertrams Bernd Schmeck |
| author_sort |
Christina E. Herkt |
| title |
A MicroRNA Network Controls <italic toggle="yes">Legionella pneumophila</italic> Replication in Human Macrophages via LGALS8 and MX1 |
| title_short |
A MicroRNA Network Controls <italic toggle="yes">Legionella pneumophila</italic> Replication in Human Macrophages via LGALS8 and MX1 |
| title_full |
A MicroRNA Network Controls <italic toggle="yes">Legionella pneumophila</italic> Replication in Human Macrophages via LGALS8 and MX1 |
| title_fullStr |
A MicroRNA Network Controls <italic toggle="yes">Legionella pneumophila</italic> Replication in Human Macrophages via LGALS8 and MX1 |
| title_full_unstemmed |
A MicroRNA Network Controls <italic toggle="yes">Legionella pneumophila</italic> Replication in Human Macrophages via LGALS8 and MX1 |
| title_sort |
microrna network controls <italic toggle="yes">legionella pneumophila</italic> replication in human macrophages via lgals8 and mx1 |
| publisher |
American Society for Microbiology |
| publishDate |
2020 |
| url |
https://doaj.org/article/f562f453df8b4591a2a3cac252c1f3ca |
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