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Published on: June 25, 2015
Tetracycline Antibiotics Induce Host-Dependent Disease Tolerance to Infection
Henrique G Colaço1, André Barros1, Ana Neves-Costa1
1Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, 2780-156 Oeiras, Portugal.
Abstract:
Several classes of antibiotics 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, which target the mitoribosome, protected against sepsis without affecting the pathogen load. Mechanistically, we found that mitochondrial inhibition of protein synthesis perturbed the electron transport chain (ETC) decreasing tissue damage in the lung and increasing fatty acid oxidation and glucocorticoid sensitivity in the liver. Using a liver-specific partial and acute deletion of Crif1, a critical mitoribosomal component for protein synthesis, we found that mice were protected against sepsis, an observation that was phenocopied by the transient inhibition of complex I of the ETC by phenformin. Together, we demonstrate that mitoribosome-targeting antibiotics are beneficial beyond their antibacterial activity and that mitochondrial protein synthesis inhibition leading to ETC perturbation is a mechanism for the induction of disease tolerance.
Insights
Tetracycline antibiotics protect against sepsis by targeting mitochondria, not just pathogens. This mechanism involves inhibiting mitochondrial protein synthesis, which reduces tissue damage and alters liver metabolism, offering a new approach to disease tolerance.
Area of Science:
- Biochemistry
- Pharmacology
- Immunology
Background:
- Antibiotics possess beneficial effects beyond pathogen clearance.
- Mitochondrial functions are increasingly recognized as therapeutic targets.
Purpose of the Study:
- To investigate the non-antibacterial effects of tetracycline antibiotics.
- To elucidate the mechanism by which mitoribosome-targeting antibiotics confer protection against sepsis.
Main Methods:
- Treatment with tetracycline antibiotics in a sepsis model.
- Analysis of pathogen load, mitochondrial protein synthesis, electron transport chain (ETC) activity, and tissue-specific metabolic changes.
- Genetic deletion of a mitoribosomal component (Crif1) and pharmacological inhibition of ETC complex I (phenformin) in mice.
Main Results:
- Tetracycline antibiotics protected against sepsis without reducing pathogen load.
- Mitochondrial protein synthesis inhibition perturbed the ETC, decreasing lung damage and enhancing liver fatty acid oxidation and glucocorticoid sensitivity.
- Mice with Crif1 deletion or treated with phenformin showed protection against sepsis.
Conclusions:
- Mitoribosome-targeting antibiotics offer benefits independent of their antibacterial activity.
- Inhibition of mitochondrial protein synthesis and subsequent ETC perturbation is a key mechanism for inducing disease tolerance.
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