A MicroRNA Network Controls Legionella pneumophila Replication in Human Macrophages via LGALS8 and MX1

Herkt，Christina E.1; Caffrey，Brian E.2; Surmann，Kristin3; Blankenburg，Sascha3; Gesell Salazar，Manuela3; Jung，Anna L.1; Herbel，Stefanie M.1; Hoffmann，Kerstin1; Schulte，Leon N.4; Chen，Wei5; Sittka-Stark，Alexandra1; Völker，Uwe3; Vingron，Martin2; Marsico，Annalisa2,6; Bertrams，Wilhelm1; Schmeck，Bernd1,7,8,9

2020-03-24

10.1128/mBio.03155-19

mBio   影响因子和分区

2150-7511

2150-7511

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.

bacteria DDX58 galectin-8 infection infectious disease inflammation Legionella pneumophila macrophage macrophages microRNA miRNA MX1 RIG-I TP53

SCI

英语

其他

Bundesministerium fur Bildung und Forschung[e:Med CAPSYS-FKZ 01ZX1604E][01ZX1304G][JPI-AMR-FKZ 01Kl1702][ERACoSysMed2-SysMed-COPD-FKZ 031L0140] ; Deutsche Forschungsgemeinschaft[SFB/TR-84 TP C01][SFB/TR-84 TP C10] ; Von-Behring-Rontgen-Stiftung[FKZ 63-0036] ; Hessisches Ministerium fur Wissenschaft und Kunst [LOEWE Medical RNomics][FKZ 519/03/00.001-(0003)]

Microbiology

Microbiology

WOS:000531071300044

AMER SOC MICROBIOLOGY

2-s2.0-85082380749

Scopus

1.Institute for Lung Research,Universities of Giessen and Marburg Lung Center,Philipps University Marburg,Marburg,Germany
2.Computational Molecular Biology,Max Planck Institute for Molecular Genetics,Germany
3.Department of Functional Genomics,Greifswald,University Medicine Greifswald,Germany
4.Institute for Lung Research/iLung,Research Group RNA-Biology of Inflammation and Infection,Philipps University,Marburg,Germany
5.Department of Biology,Southern University of Science and Technology,Shenzhen,China
6.Institute of Computational Biology,Helmholtz Zentrum Muenchen,Neuherberg,Germany
7.Department of Medicine,Pulmonary and Critical Care Medicine,University Medical Center Giessen and Marburg,Philipps University,Marburg,Germany
8.Center for Synthetic Microbiology (SYNMIKRO),Philipps University Marburg,Marburg,Germany
9.German Center for Infection Research (DZIF),Marburg,partner site Giessen-Marburg-Langen,Germany

Herkt，Christina E.,Caffrey，Brian E.,Surmann，Kristin,et al. A MicroRNA Network Controls Legionella pneumophila Replication in Human Macrophages via LGALS8 and MX1[J]. mBio,2020,11(2).

Herkt，Christina E..,Caffrey，Brian E..,Surmann，Kristin.,Blankenburg，Sascha.,Gesell Salazar，Manuela.,...&Schmeck，Bernd.(2020).A MicroRNA Network Controls Legionella pneumophila Replication in Human Macrophages via LGALS8 and MX1.mBio,11(2).

Herkt，Christina E.,et al."A MicroRNA Network Controls Legionella pneumophila Replication in Human Macrophages via LGALS8 and MX1".mBio 11.2(2020).