Many respiratory infections, such as influenza or COVID-19, cause significant stress to cells and organs, culminating in acute respiratory distress syndrome (ARDS) and, in the elderly or frail, death.
“Rather than attacking the infectious agent, novel treatment techniques for ARDS might strive to elicit the host organism’s tolerance to the inflammatory challenge by increasing its natural adaptive stress responses,” says Professor Johan Auwerx of EPFL’s School of Life Sciences. Adrienne Mottis of EPFL and her colleagues demonstrated in a new study that one such method can take advantage of a biological phenomena known as “mitohormesis.”
Mitohormesis is the process by which modest stress to a cell’s mitochondria causes a cascade of reactions that actually improves the cell’s health and survival.
Mitochondria are the primary energy-harvesting organelles in the cell, and as such, they are continually watched by the cell’s “surveillance” systems. If the mitochondria fail or are stressed, this constant quality monitoring might trigger adaptive compensating reactions known as “mitochondrial stress responses.”
“A low amount of mitochondrial stress might thus be advantageous overall for the cell and the organism since the good effect of these stress responses can override the unfavourable effect of the initial stressor,” says Mottis, the study’s principal investigator.
Previous research has shown that inducing mitohormesis can increase longevity by counteracting the effects of age-related or metabolic illnesses.
Antibiotics are effective against mitochondria since they developed from bacteria. As a result, the researchers investigated various antibiotics that could stress mitochondria and discovered novel molecules in the tetracycline family, a class of antibiotics that inhibits the synthesis of mitochondrial proteins and is used to treat a variety of infections such as acne, cholera, plague, malaria, and syphilis.
The researchers tested 52 tetracyclines and chose unique compounds like 9-test-butyldoxycycline (9-TB) that are very effective at eliciting mitohormesis even at low dosages while having no antibiotic impact – that is, they do not disrupt the host’s microbiota.
The chemicals induced modest mitochondrial stress and favourable mitohormetic responses in mice, increasing the animals’ tolerance to influenza virus infection.
“Most critically, our findings reveal that 9-TB-induced mitochondrial responses activate the ATF4 signalling pathway, a well-described response to several cellular stresses, as well as innate immune signalling pathways, the so-called type I interferon response,” Auwerx says. “As a consequence, 9-TB increased the lifespan of mice exposed to a deadly influenza illness while having no effect on viral load. Resistant hosts fight infection by inducing an immune response that decreases pathogen load, whereas tolerance refers to mechanisms that limit the level of organ dysfunction and tissue damage produced by infection without necessarily influencing pathogen burden.”
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According to the findings, 9-TB can establish tolerance to influenza infection in mice by lowering the level of inflammation and tissue damage while without changing their microbiota. These discoveries bring up new treatment possibilities by focusing on mitochondria and mitohormesis.
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