Tetracycline-induced mitohormesis mediates disease tolerance against influenza
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
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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Research Article Infectious disease

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 5

9-TB does not impact gut microbiome and shows encouraging effects when therapeutically administered.

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9-TB does not impact gut microbiome and shows encouraging effects when t...
(A) Comparison of bacterial community composition by nonmetric multidimensional scaling (NMDS) based on the Bray-Curtis dissimilarity. (B) Comparison of bacterial species diversity in terms of Shannon diversity index (SDI) and richness. The lower and upper hinges are the first and third quartiles. The middle line is the median. The upper and lower whiskers respectively represent the highest and lowest values that are within 1.5× IQR from the hinge, where IQR is the interquartile range (i.e., distance between the first and third quartile). Data points beyond whiskers are considered outliers. Statistical significance assessed by Kruskal-Wallis test and post hoc Wilcoxon’s test with P values adjusted for multiple comparison using the Holm-Bonferroni method. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. NS, P > 0.05. (C and D) Eight-week-old BALB/cN mice (n = 12) were infected intranasally with 760 PFU of IFV H1N1 PR8 and injected with 9-TB (0.05, 0.025 mpkd), as described in Supplemental Figure 5A. Survival (C) and clinical score (D) were followed for 14 days after infection (n = 12). Statistical analysis was performed by log-rank (Mantel-Cox) test (C) or 1-way ANOVA followed by Tukey’s post hoc test (D). Error bars represent ±SEM.