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

: Almeida, L.; Dhillon-LaBrooy, A.; Castro, C.N.; Ayele, N.; Bartel, J.; Carriche, G.M.; Guderian, M.; Lippens, S.; Dennerlein, S.; Hesse, Christina; Lambrecht, Bart N.; Schauser, L.; Blazar, B.R.; Kalesse, Markus; Müller, R.; Moita, L.F.; Sparwasser, T.

Preprint urn:nbn:de:0011-n-5746704 (1.8 MByte PDF)
MD5 Fingerprint: bbcdb72d18e88010e4b60f653e81dc60
Created on: 29.1.2020

bioRxiv. The preprint server for biology. Online resource (2019), 40 pp.
Journal Article, Electronic Publication
Fraunhofer ITEM ()

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.