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.

中文翻译：

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四环素诱导的有丝分裂介导对流感的疾病耐受性

有丝分裂定义了由对轻度线粒体应激的适应性反应介导的适应性增加。四环素不仅抑制细菌，而且抑制线粒体翻译，从而对真核细胞施加低水平的线粒体压力。我们在细胞和无菌小鼠模型中证明，四环素诱导温和的适应性线粒体应激反应 (MSR)，包括 ATF4 介导的综合应激反应和 I 型干扰素 (IFN) 信号传导。为了克服四环素对宿主微生物组的干扰，我们鉴定了具有最小抗菌活性但仍保留诱导 MSR 的全部能力的四环素衍生物，例如先导化合物 9- tert-丁基强力霉素（9-TB）。多西环素 (Dox) 和 9-TB 诱导的 MSR 在预防性给药时可提高对致命流感病毒 (IFV) 感染的存活率和疾病耐受性。与 Dox 不同，9-TB 不会影响肠道微生物组，并且在治疗环境中给予 IFV 时也显示出令人鼓舞的结果。对 IFV 感染的耐受性与参与肺上皮细胞和纤毛功能的基因的诱导有关，并与肺、肝和肾中炎症和免疫基因组的下调有关。由非抗菌四环素引起的有丝分裂和随后的 IFN 反应可能会抑制病毒感染期间的过度炎症和组织损伤，从而开辟创新的治疗途径。