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Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis.

Authors
  • Almeida, Luís1
  • Dhillon-LaBrooy, Ayesha1
  • Castro, Carla N2
  • Adossa, Nigatu3
  • Carriche, Guilhermina M1
  • Guderian, Melanie2
  • Lippens, Saskia4
  • Dennerlein, Sven5
  • Hesse, Christina6
  • Lambrecht, Bart N7
  • Berod, Luciana8
  • Schauser, Leif9
  • Blazar, Bruce R10
  • Kalesse, Markus11
  • Müller, Rolf12
  • Moita, Luís F13
  • Sparwasser, Tim14
  • 1 Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research, Hannover Medical School and the Helmholtz Center for Infection Research, Hannover 30625, Germany; Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany. , (Germany)
  • 2 Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research, Hannover Medical School and the Helmholtz Center for Infection Research, Hannover 30625, Germany. , (Germany)
  • 3 QIAGEN, Aarhus C 8000, Denmark; University of Turku, Computational Biomedicine, Turku Center for Biotechnology, Turku 20520, Finland. , (Denmark)
  • 4 VIB Imaging Core Facility Gent, Gent 9052, Belgium. , (Belgium)
  • 5 Department of Cellular Biochemistry, University Medical Center, Göttingen 37073, Germany. , (Germany)
  • 6 Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover 30625, Germany. , (Germany)
  • 7 VIB-UGent, Center for Inflammation Research, Gent 9052, Belgium. , (Belgium)
  • 8 Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research, Hannover Medical School and the Helmholtz Center for Infection Research, Hannover 30625, Germany; Institute of Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. , (Germany)
  • 9 QIAGEN, Aarhus C 8000, Denmark. , (Denmark)
  • 10 Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55454, USA.
  • 11 Institute for Organic Chemistry, Leibniz University Hannover, Hannover, Germany; Helmholtz Center for Infection Research (HZI), Braunschweig 38124, Germany. , (Germany)
  • 12 Helmholtz Institute for Pharmaceutical Research, Helmholtz Center for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken 66123, Germany. , (Germany)
  • 13 Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal. , (Portugal)
  • 14 Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research, Hannover Medical School and the Helmholtz Center for Infection Research, Hannover 30625, Germany; Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany. Electronic address: [email protected] , (Germany)
Type
Published Article
Journal
Immunity
Publication Date
Nov 24, 2020
Identifiers
DOI: 10.1016/j.immuni.2020.11.001
PMID: 33238133
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive for reasons that remain unclear. Here, we show that Linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease. Linezolid and other RAbos were strong inhibitors of T helper-17 cell effector function in vitro, showing that this effect was independent of their antibiotic activity. Perturbing mitochondrial translation in differentiating T cells, either with RAbos or through the inhibition of mitochondrial elongation factor G1 (mEF-G1) progressively compromised the integrity of the electron transport chain. Ultimately, this led to deficient oxidative phosphorylation, diminishing nicotinamide adenine dinucleotide concentrations and impairing cytokine production in differentiating T cells. In accordance, mice lacking mEF-G1 in T cells were protected from experimental autoimmune encephalomyelitis, demonstrating that this pathway is crucial in maintaining T cell function and pathogenicity. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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