{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:41:05Z","timestamp":1772156465284,"version":"3.50.1"},"posted":{"date-parts":[[2019,11,7]]},"group-title":"Immunology","reference-count":74,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2019,11,7]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Synergy of resistance and disease tolerance mechanisms is necessary for an effective immune response leading to survival and return to homeostasis when an organism is challenged by infection. Antibiotics are used for their resistance enhancement capabilities by decreasing pathogen load, but several classes have long been known to have beneficial effects that cannot be explained strictly on the basis of their capacity to control the infectious agent. Here we report that tetracycline antibiotics, a class of ribosome-targeting drugs, robustly protects against sepsis by inducing disease tolerance, independently from their direct antibiotic properties. Mechanistically, we find that mitochondrial inhibition of protein synthesis perturbs the electron transfer chain and leads to improved damage repair in the lung and fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a partial and acute deletion of\n                  <jats:italic>CRIF1<\/jats:italic>\n                  in the liver, a critical mitoribosomal component for protein synthesis, we find that mice are protected against bacterial sepsis, an observation which is phenocopied by the transient inhibition of complex I of ETC by phenformin. Together, we demonstrate that ribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a novel mechanism for the induction of disease tolerance.\n                <\/jats:p>","DOI":"10.1101\/833269","type":"posted-content","created":{"date-parts":[[2019,11,8]],"date-time":"2019-11-08T11:22:00Z","timestamp":1573212120000},"source":"Crossref","is-referenced-by-count":1,"title":["Host-dependent induction of disease tolerance to infection by tetracycline antibiotics"],"prefix":"10.64898","author":[{"given":"Henrique G.","family":"Cola\u00e7o","sequence":"first","affiliation":[]},{"given":"Andr\u00e9","family":"Barros","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Neves-Costa","sequence":"additional","affiliation":[]},{"given":"Elsa","family":"Seixas","sequence":"additional","affiliation":[]},{"given":"Dora","family":"Pedroso","sequence":"additional","affiliation":[]},{"given":"Tiago R.","family":"Velho","sequence":"additional","affiliation":[]},{"given":"Katharina","family":"Willmann","sequence":"additional","affiliation":[]},{"given":"Hyon-Seung","family":"Yi","sequence":"additional","affiliation":[]},{"given":"Minho","family":"Shong","sequence":"additional","affiliation":[]},{"given":"Vladimir","family":"Benes","sequence":"additional","affiliation":[]},{"given":"Sebastian","family":"Weis","sequence":"additional","affiliation":[]},{"given":"Thomas","family":"K\u00f6cher","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0707-315X","authenticated-orcid":false,"given":"Lu\u00eds F.","family":"Moita","sequence":"additional","affiliation":[]}],"member":"54368","reference":[{"key":"2019110906450430000_833269v1.1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.7.3336"},{"key":"2019110906450430000_833269v1.2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2011-0364OC"},{"key":"2019110906450430000_833269v1.3","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200606000-00016"},{"key":"2019110906450430000_833269v1.4","first-page":"1","article-title":"Seminar Sepsis and septic shock","volume":"6736","year":"2018","journal-title":"Lancet"},{"key":"2019110906450430000_833269v1.5","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.stemcr.2014.06.013","article-title":"Doxycycline enhances survival and self-renewal of human pluripotent stem cells","volume":"3","year":"2014","journal-title":"Stem Cell Reports"},{"key":"2019110906450430000_833269v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.03.030"},{"key":"2019110906450430000_833269v1.7","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/dvdy.24522","article-title":"Neurodegeneration in ataxia-telangiectasia: Multiple roles of ATM kinase in cellular homeostasis","volume":"247","year":"2018","journal-title":"Dev. Dyn"},{"key":"2019110906450430000_833269v1.8","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201607110"},{"key":"2019110906450430000_833269v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)70112-X"},{"key":"2019110906450430000_833269v1.10","doi-asserted-by":"crossref","first-page":"2448","DOI":"10.1111\/febs.13730","article-title":"Initiation of innate immune responses by surveillance of homeostasis perturbations","volume":"283","year":"2016","journal-title":"FEBS J"},{"key":"2019110906450430000_833269v1.11","doi-asserted-by":"crossref","unstructured":"Deepa, S.S. , Pharaoh, G. , Kinter, M. , Diaz, V. , Fok, W.C. , Riddle, K. , Pulliam, D. , Hill, S. , Fischer, K.E. , Soto, V. , et al. (2018). Lifelong reduction in complex IV induces tissue-specific metabolic effects but does not reduce lifespan or healthspan in mice. Aging Cell 17.","DOI":"10.1111\/acel.12769"},{"key":"2019110906450430000_833269v1.12","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cytogfr.2017.04.002","article-title":"Glucocorticoid resistance as a major drive in sepsis pathology","volume":"35","year":"2017","journal-title":"Cytokine Growth Factor Rev"},{"key":"2019110906450430000_833269v1.13","first-page":"201821565","article-title":"TNF-\u03b1 inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile","volume":"116","year":"2019","journal-title":"Proc. Natl. Acad. Sci"},{"key":"2019110906450430000_833269v1.14","doi-asserted-by":"publisher","DOI":"10.1126\/science.1077780"},{"key":"2019110906450430000_833269v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.06.001"},{"key":"2019110906450430000_833269v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2019110906450430000_833269v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.95"},{"key":"2019110906450430000_833269v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.12.016"},{"key":"2019110906450430000_833269v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2008.08.013"},{"key":"2019110906450430000_833269v1.20","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw354"},{"key":"2019110906450430000_833269v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.08.039"},{"key":"2019110906450430000_833269v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2016.06.002"},{"key":"2019110906450430000_833269v1.23","unstructured":"Fleury, S. , Mesotten, D. , Wahli, W. , Bouchaert, E. , Staels, B. , Bauge, E. , Guillou, H. , Smati, S. , Tailleux, A. , Hennuyer, N. , et al. (2019). Hepatic PPAR\u03b1 is critical in the metabolic adaptation to sepsis. J. Hepatol."},{"key":"2019110906450430000_833269v1.24","doi-asserted-by":"publisher","DOI":"10.4161\/auto.19716"},{"key":"2019110906450430000_833269v1.25","doi-asserted-by":"publisher","DOI":"10.1186\/cc7780"},{"key":"2019110906450430000_833269v1.26","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-015-0980-0"},{"key":"2019110906450430000_833269v1.27","doi-asserted-by":"crossref","unstructured":"Ganeshan, K. , Nikkanen, J. , Man, K. , Leong, Y.A. , Sogawa, Y. , Maschek, J.A. , Van Ry, T. , Chagwedera, D.N. , Cox, J.E. , and Chawla, A. (2019). Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance. Cell 1\u201315.","DOI":"10.1016\/j.cell.2019.01.050"},{"key":"2019110906450430000_833269v1.28","doi-asserted-by":"publisher","DOI":"10.1007\/BF00328721"},{"key":"2019110906450430000_833269v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3229"},{"key":"2019110906450430000_833269v1.30","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.3389\/fimmu.2018.02042","article-title":"Therapeutic Potential of the Gut Microbiota in the Prevention and Treatment of Sepsis","volume":"9","year":"2018","journal-title":"Front. Immunol"},{"key":"2019110906450430000_833269v1.31","doi-asserted-by":"crossref","unstructured":"Hackett, N.R. , Shaykhiev, R. , Walters, M.S. , Wang, R. , Zwick, R.K. , Ferris, B. , Witover, B. , Salit, J. , and Crystal, R.G. (2011). The human airway epithelial basal cell transcriptome. PLoS One 6.","DOI":"10.1371\/journal.pone.0018378"},{"key":"2019110906450430000_833269v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/nature12188"},{"key":"2019110906450430000_833269v1.33","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3006055"},{"key":"2019110906450430000_833269v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/366461a0"},{"key":"2019110906450430000_833269v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.06.012"},{"key":"2019110906450430000_833269v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601986"},{"key":"2019110906450430000_833269v1.37","doi-asserted-by":"crossref","first-page":"432","DOI":"10.4161\/auto.23026","article-title":"The NLR protein, NLRX1, and its partner, TUFM, reduce type I interferon, and enhance autophagy","volume":"9","year":"2013","journal-title":"Autophagy"},{"key":"2019110906450430000_833269v1.38","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-062917-011942"},{"key":"2019110906450430000_833269v1.39","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2019110906450430000_833269v1.40","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.cmet.2018.01.018","article-title":"Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits","volume":"27","year":"2018","journal-title":"Cell Metab"},{"key":"2019110906450430000_833269v1.41","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.immuni.2013.10.012","article-title":"Septic Shock: On the importance of being tolerant","volume":"39","year":"2013","journal-title":"Immunity"},{"key":"2019110906450430000_833269v1.42","unstructured":"Medzhitov, R. (2019). An evolutionary perspective on immunometabolism. Science (80-.)."},{"key":"2019110906450430000_833269v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2015.01.005"},{"key":"2019110906450430000_833269v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.02.034"},{"key":"2019110906450430000_833269v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.021"},{"key":"2019110906450430000_833269v1.46","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1046\/j.1365-3156.2002.00941.x","article-title":"Tolerability of doxycycline monohydrate salt vs. chloroquine-proguanil in malaria chemoprophylaxis","volume":"7","year":"2002","journal-title":"Trop. Med. Int. Heal"},{"key":"2019110906450430000_833269v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/nm1586"},{"key":"2019110906450430000_833269v1.48","doi-asserted-by":"crossref","unstructured":"Paumelle, R. , Haas, J.T. , Hennuyer, N. , Baug\u00e9, E. , Deleye, Y. , Mesotten, D. , Langouche, L. , Vanhoutte, J. , Cudejko, C. , Wouters, K. , et al. (2019). Hepatic PPAR\u03b1 is critical in the metabolic adaptation to sepsis. J. Hepatol. 963\u2013973.","DOI":"10.1016\/j.jhep.2018.12.037"},{"key":"2019110906450430000_833269v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.08.047"},{"key":"2019110906450430000_833269v1.50","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R117.791061"},{"key":"2019110906450430000_833269v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.06.034"},{"key":"2019110906450430000_833269v1.52","doi-asserted-by":"publisher","DOI":"10.1378\/chest.125.2_suppl.70S"},{"key":"2019110906450430000_833269v1.53","doi-asserted-by":"publisher","DOI":"10.1586\/eri.11.141"},{"key":"2019110906450430000_833269v1.54","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1097\/SHK.0000000000000603","article-title":"Cellular Stress Responses and Monitored Cellular Activities","volume":"46","year":"2016","journal-title":"Shock"},{"key":"2019110906450430000_833269v1.55","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac6468"},{"key":"2019110906450430000_833269v1.56","first-page":"107","article-title":"Immunomodulatory effects of macrolide antibiotics in respiratory disease: Therapeutic implications for asthma and cystic fibrosis. Pediatr","volume":"9","year":"2007","journal-title":"Drugs"},{"key":"2019110906450430000_833269v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2013.04.007"},{"key":"2019110906450430000_833269v1.58","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (sepsis-3)","volume":"315","year":"2016","journal-title":"JAMA - J. Am. Med. Assoc"},{"key":"2019110906450430000_833269v1.59","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.136"},{"key":"2019110906450430000_833269v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.058"},{"key":"2019110906450430000_833269v1.61","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/kxw041"},{"key":"2019110906450430000_833269v1.62","doi-asserted-by":"publisher","DOI":"10.2174\/1874467210801010068"},{"key":"2019110906450430000_833269v1.63","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1001\/jama.2016.2691","article-title":"Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis","volume":"315","year":"2016","journal-title":"JAMA - J. Am. Med. Assoc"},{"key":"2019110906450430000_833269v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.07.026"},{"key":"2019110906450430000_833269v1.65","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.cell.2017.05.031","article-title":"Metabolic Adaptation Establishes Disease Tolerance to Sepsis","volume":"169","year":"2017","journal-title":"Cell"},{"key":"2019110906450430000_833269v1.66","doi-asserted-by":"publisher","DOI":"10.4161\/viru.25436"},{"key":"2019110906450430000_833269v1.67","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2004.02.028"},{"key":"2019110906450430000_833269v1.68","unstructured":"Wyngene, L. Van , Vandewalle, J. , and Libert, C. Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last ?"},{"key":"2019110906450430000_833269v1.69","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201708712"},{"key":"2019110906450430000_833269v1.70","doi-asserted-by":"publisher","DOI":"10.4161\/cc.11.5.19328"},{"key":"2019110906450430000_833269v1.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.01.011"},{"key":"2019110906450430000_833269v1.72","first-page":"3","article-title":"Mitochondrial electron transport chain, ROS generation and uncoupling (Review)","volume":"44","year":"2019","journal-title":"Int. J. Mol. Med"},{"key":"2019110906450430000_833269v1.73","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-6644com"},{"key":"2019110906450430000_833269v1.74","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nature13903","article-title":"P63 + Krt5 + distal airway stem cells are essential for lung regeneration","volume":"517","year":"2015","journal-title":"Nature"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/833269","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T23:41:00Z","timestamp":1768434060000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/833269"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,7]]},"references-count":74,"URL":"https:\/\/doi.org\/10.1101\/833269","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.immuni.2020.09.011","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.3410\/f.736910339.793573314","asserted-by":"object"}]},"subject":[],"published":{"date-parts":[[2019,11,7]]},"subtype":"preprint"}}