Tetracycline-induced mitohormesis mediates disease tolerance against influenza
Adrienne Mottis, … , Mark L. Nelson, Johan Auwerx
Adrienne Mottis, … , Mark L. Nelson, Johan Auwerx
Published July 5, 2022
Citation Information: J Clin Invest. 2022;132(17):e151540. https://doi.org/10.1172/JCI151540.
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Tetracycline-induced mitohormesis mediates disease tolerance against influenza

Abstract

Mitohormesis defines the increase in fitness mediated by adaptive responses to mild mitochondrial stress. Tetracyclines inhibit not only bacterial but also mitochondrial translation, thus imposing a low level of mitochondrial stress on eukaryotic cells. We demonstrate in cell and germ-free mouse models that tetracyclines induce a mild adaptive mitochondrial stress response (MSR), involving both the ATF4-mediated integrative stress response and type I interferon (IFN) signaling. To overcome the interferences of tetracyclines with the host microbiome, we identify tetracycline derivatives that have minimal antimicrobial activity, yet retain full capacity to induce the MSR, such as the lead compound, 9-tert-butyl doxycycline (9-TB). The MSR induced by doxycycline (Dox) and 9-TB improves survival and disease tolerance against lethal influenza virus (IFV) infection when given preventively. 9-TB, unlike Dox, did not affect the gut microbiome and also showed encouraging results against IFV when given in a therapeutic setting. Tolerance to IFV infection is associated with the induction of genes involved in lung epithelial cell and cilia function, and with downregulation of inflammatory and immune gene sets in lungs, liver, and kidneys. Mitohormesis induced by non-antimicrobial tetracyclines and the ensuing IFN response may dampen excessive inflammation and tissue damage during viral infections, opening innovative therapeutic avenues.

Authors

Adrienne Mottis, Terytty Y. Li, Gaby El Alam, Alexis Rapin, Elena Katsyuba, David Liaskos, Davide D’Amico, Nicola L. Harris, Mark C. Grier, Laurent Mouchiroud, Mark L. Nelson, Johan Auwerx

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Figure 3

Tet derivatives induce the MSR and type I IFN signalling in mammalian cells.

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Tet derivatives induce the MSR and type I IFN signalling in mammalian ce...
(A–C) Tet derivatives induce a mitochondrial/nuclear protein imbalance and the MSR in HEK293T cells (human) treated for 24 hours at the indicated concentrations. (A) Immunoblots of HEK293T cells for the OXPHOS subunits ATP5A (encoded in nuclear DNA) and MTCO1 (encoded in mtDNA) with tubulin serving as a control. Quantification of the relative MTCO1/ATP5A ratio is shown on the right. (B) Oxygen consumption rate of HEK293T cells exposed to different concentrations of Dox, 9-TB, or ATc (n = 8). (C) Transcript levels of the indicated MSR genes measured by RT-qPCR (n = 4). (D and E) Tet derivatives induce transcript levels of the indicated ISGs (D) and stimulate IFN-β secretion (E) after 24 hours of treatment at the indicated concentrations in mouse BMDMs (day 6 differentiation) (n = 4). Statistical analysis was performed by 1-way ANOVA (B, D, and E) or 2-way ANOVA (C) followed by Tukey’s post hoc test . *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001. Error bars represent ±SEM.