Tetracycline-induced mitohormesis mediates disease tolerance against influenza
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 mod...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-09-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI151540 |
| _version_ | 1827768258195881984 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Adrienne Mottis |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:09:44Z |
| format | Article |
| id | doaj.art-640bce408e454dcb9f479983b78136ee |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:44Z |
| publishDate | 2022-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-640bce408e454dcb9f479983b78136ee2023-11-07T16:19:17ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-09-0113217Tetracycline-induced mitohormesis mediates disease tolerance against influenzaAdrienne MottisTerytty Y. LiGaby El AlamAlexis RapinElena KatsyubaDavid LiaskosDavide D’AmicoNicola L. HarrisMark C. GrierLaurent MouchiroudMark L. NelsonJohan AuwerxMitohormesis 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.https://doi.org/10.1172/JCI151540Infectious disease |
| spellingShingle | 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 Tetracycline-induced mitohormesis mediates disease tolerance against influenza The Journal of Clinical Investigation Infectious disease |
| title | Tetracycline-induced mitohormesis mediates disease tolerance against influenza |
| title_full | Tetracycline-induced mitohormesis mediates disease tolerance against influenza |
| title_fullStr | Tetracycline-induced mitohormesis mediates disease tolerance against influenza |
| title_full_unstemmed | Tetracycline-induced mitohormesis mediates disease tolerance against influenza |
| title_short | Tetracycline-induced mitohormesis mediates disease tolerance against influenza |
| title_sort | tetracycline induced mitohormesis mediates disease tolerance against influenza |
| topic | Infectious disease |
| url | https://doi.org/10.1172/JCI151540 |
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