PuSH - Publication Server of Helmholtz Zentrum München: A miRNA network controls <em>Legionella pneumophila</em> replication in human macrophages via LGALS8 and MX1.

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Herkt, C.E.* ; Caffrey, B.E.* ; Surmann, K.* ; Blankenburg, S.* ; Gesell Salazar, M.* ; Jung, A.L.* ; Herbel, S.M.* ; Hoffmann, K.* ; Schulte, L.N.* ; Chen, W.* ; Sittka-Stark, A.* ; Völker, U.* ; Vingron, M.* ; Marsico, A. ; Bertrams, W.* ; Schmeck, B.*

A miRNA network controls Legionella pneumophila replication in human macrophages via LGALS8 and MX1.

mBio 11:e03155-19 (2020)

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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. pneurnophila 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-1, 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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Mirna ; Infection ; Macrophage ; Mx1 ; Bacteria ; Galectin-8 ; Legionella; Guanylate Binding-proteins; Nf-kappa-b; Helicobacter-pylori; Negative Regulator; Tumor-suppressor; Epithelial-cells; Gene-expression; Interferon; Virus; P53

ISSN (print) / ISBN 2150-7511

e-ISSN 2150-7511

Journal mBio

Quellenangaben Volume: 11, Issue: 2, Article Number: e03155-19

Publisher American Society for Microbiology (ASM)

Publishing Place 1752 N St Nw, Washington, Dc 20036-2904 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)