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Host-dependent induction of disease tolerance to infection by tetracycline antibiotics

Henrique G. Colaço, André Barros, Ana Neves-Costa, Elsa Seixas, Dora Pedroso, Tiago R. Velho, Katharina Willmann, Hyon-Seung Yi, Minho Shong, Vladimir Benes, Sebastian Weis, Thomas Köcher, View ORCID ProfileLuís F. Moita
doi: https://doi.org/10.1101/833269
Henrique G. Colaço
1Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal
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André Barros
1Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal
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Ana Neves-Costa
1Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal
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Elsa Seixas
1Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal
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Dora Pedroso
1Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal
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Tiago R. Velho
1Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal
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Katharina Willmann
1Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal
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Hyon-Seung Yi
2Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 35015, Korea
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Minho Shong
2Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 35015, Korea
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Vladimir Benes
3EMBL Genomics Core Facilities, D-69117 Heidelberg, Germany
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Sebastian Weis
4Institute for Infectious Disease and Infection Control, Jena University Hospital
5Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital
6Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany
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Thomas Köcher
7Vienna BioCenter Core Facilities GmbH, 1030 Vienna, Austria
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Luís F. Moita
1Innate Immunity and Inflammation Laboratory, Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal
8Instituto de Histologia e Biologia do Desenvolvimento, Faculdade de Medicina, Universidade de Lisboa, Portugal
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  • ORCID record for Luís F. Moita
  • For correspondence: lmoita@igc.gulbenkian.pt
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Summary

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 CRIF1 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.

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Posted November 07, 2019.
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Host-dependent induction of disease tolerance to infection by tetracycline antibiotics
Henrique G. Colaço, André Barros, Ana Neves-Costa, Elsa Seixas, Dora Pedroso, Tiago R. Velho, Katharina Willmann, Hyon-Seung Yi, Minho Shong, Vladimir Benes, Sebastian Weis, Thomas Köcher, Luís F. Moita
bioRxiv 833269; doi: https://doi.org/10.1101/833269
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Host-dependent induction of disease tolerance to infection by tetracycline antibiotics
Henrique G. Colaço, André Barros, Ana Neves-Costa, Elsa Seixas, Dora Pedroso, Tiago R. Velho, Katharina Willmann, Hyon-Seung Yi, Minho Shong, Vladimir Benes, Sebastian Weis, Thomas Köcher, Luís F. Moita
bioRxiv 833269; doi: https://doi.org/10.1101/833269

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