1. Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis.
- Author
-
Almeida L, Dhillon-LaBrooy A, Castro CN, Adossa N, Carriche GM, Guderian M, Lippens S, Dennerlein S, Hesse C, Lambrecht BN, Berod L, Schauser L, Blazar BR, Kalesse M, Müller R, Moita LF, and Sparwasser T
- Subjects
- Animals, Autoimmunity drug effects, Cell Differentiation, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria genetics, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Molecular Targeted Therapy, Multiple Sclerosis drug therapy, NAD metabolism, Oxidative Phosphorylation, Peptide Elongation Factor G genetics, Peptide Elongation Factor G metabolism, Anti-Bacterial Agents therapeutic use, Encephalomyelitis, Autoimmune, Experimental drug therapy, Linezolid therapeutic use, Mitochondria metabolism, Peptides, Cyclic therapeutic use, Ribosomes metabolism, Th17 Cells physiology
- 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., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF