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Ribosome-targeting antibiotics impair T cell effector function and ameliorate autoimmunity by blocking mitochondrial protein synthesis

L Almeida, A Dhillon-LaBrooy, CN Castro, N Ayele, J Bartel, GM Carriche, M Guderian, S Lippens, S Dennerlein, C Hesse, BN Lambrecht, L Schauser, BR Blazar, M Kalesse, R Müller, LF Moita, T Sparwasser
doi: https://doi.org/10.1101/832956
L Almeida
1Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
2Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz 55122, Germany
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A Dhillon-LaBrooy
1Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
2Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz 55122, Germany
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CN Castro
1Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
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N Ayele
3QIAGEN, Aarhus C 8000, Denmark.
4University of Turku, Computational Biomedicine, Turku Centre for Biotechnology, Turku 20520, Finland.
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J Bartel
1Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
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GM Carriche
1Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
2Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz 55122, Germany
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M Guderian
1Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
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S Lippens
5VIB Imaging Core Facility Gent, Gent 9052, Belgium.
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S Dennerlein
6Department of Cellular Biochemistry, University Medical Centre, Göttingen 37099, Germany.
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C Hesse
7Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover 30625, Germany
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BN Lambrecht
8VIB-UGent, Center for Inflammation Research, Gent 9052, Belgium.
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L Schauser
4University of Turku, Computational Biomedicine, Turku Centre for Biotechnology, Turku 20520, Finland.
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BR Blazar
9Department of Pediatrics, Division of Blood and Marrow Transplantion, University of Minnesota, Minneapolis, MN 55454, USA.
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M Kalesse
10Institute for Organic Chemistry, Leibniz University Hannover, Hannover, Germany and Helmholtz Centre for Infection Research (HZI), Braunschweig 38124, Germany.
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R Müller
11Helmholtz Institute for Pharmaceutical Research, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken 66123, Germany.
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LF Moita
12Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciencia, Oeiras, Portugal
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T Sparwasser
1Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover 30625, Germany.
2Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz 55122, Germany
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  • For correspondence: sparwasser.office@uni-mainz.de
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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 Th17 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 compromises the integrity of the electron transport chain (ETC). Ultimately, this leads to loss of mitochondrial metabolism and cytokine production in differentiating Th cells. In accordance, mice lacking Gfm1 in T cells are protected from EAE, demonstrating that this pathway plays a key role in maintaining T cell function and pathogenicity.

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Posted November 06, 2019.
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Ribosome-targeting antibiotics impair T cell effector function and ameliorate autoimmunity by blocking mitochondrial protein synthesis
L Almeida, A Dhillon-LaBrooy, CN Castro, N Ayele, J Bartel, GM Carriche, M Guderian, S Lippens, S Dennerlein, C Hesse, BN Lambrecht, L Schauser, BR Blazar, M Kalesse, R Müller, LF Moita, T Sparwasser
bioRxiv 832956; doi: https://doi.org/10.1101/832956
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Ribosome-targeting antibiotics impair T cell effector function and ameliorate autoimmunity by blocking mitochondrial protein synthesis
L Almeida, A Dhillon-LaBrooy, CN Castro, N Ayele, J Bartel, GM Carriche, M Guderian, S Lippens, S Dennerlein, C Hesse, BN Lambrecht, L Schauser, BR Blazar, M Kalesse, R Müller, LF Moita, T Sparwasser
bioRxiv 832956; doi: https://doi.org/10.1101/832956

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