Many respiratory infections, such as the flu or COVID-19, cause significant stress to cells and organs, which can lead to acute respiratory distress syndrome (ARDS), which can eventually cause death in older or sensitive people.
“New therapeutic strategies to fight ARDS, instead of fighting an infectious agent, could try to induce host tolerance to an inflammatory challenge by enhancing its natural adaptive stress responses,” says Prof. Johan Auwerks from EPFL’s School of Life Sciences.
In a new study, EPFL’s Adrienne Mottis and her colleagues show that one such strategy could exploit a biological phenomenon known as “mitochormesis.” Mitochormesis describes the fact that mild stress to a cell’s mitochondria can trigger a series of reactions that actually increase the cell’s health and vitality.
Mitochondria are the main energy-harvesting organelles of the cell and are therefore constantly monitored by the cell’s “monitoring” systems. If mitochondria fail or are stressed, this continuous quality control can activate adaptive compensatory responses known as “mitochondrial stress responses”.
“Therefore, a mild level of mitochondrial stress may be beneficial for the cell and the organism as a whole, since the positive effect of these stress responses can overcome the negative effect of the initial stressor,” says Mottis, who led the study. This idea is supported by previous research showing that stimulating mitochormesis can increase lifespan by counteracting the effects of age-related or metabolic disturbances.
Since mitochondria originated from bacteria, they are susceptible to antibiotics. Therefore, the researchers studied various antibiotics that can cause mitochondrial stress and identified new molecules from the tetracycline family, a class of antibiotics that block the synthesis of mitochondrial proteins and are used to fight a number of infections such as acne, cholera, plague, malaria and syphilis.
The researchers analyzed 52 tetracyclines and selected new molecules, such as 9-tert-butyldoxycycline (9-TB), that are highly effective in triggering mitochormesis even at low doses, but do not have an antibiotic effect, that is, do not disrupt the host microbiome. When tested in mice, these compounds induced mild mitochondrial stress and favorable mitochormetic responses that increased the animals’ resistance to influenza virus infection.
“Most importantly, our study shows that 9-TB-induced mitochondrial responses activate the ATF4 signaling pathway, a well-characterized response to numerous cellular stressors, and also mobilize innate immune signaling pathways, the so-called type I interferon response,” adds Auwerks.
As a result, 9-TB improved the survival of mice exposed to a lethal influenza infection, but did not affect the viral load.” Resistant hosts fight infection by inducing an immune response that reduces the pathogen load, while tolerance refers to mechanisms that limit the degree of organ dysfunction and tissue damage caused by infection without necessarily affecting the pathogen load.”
The study shows that 9-TB can induce tolerance to influenza infection in mice by reducing inflammation and tissue damage without affecting their microbiome.
“These results open up innovative therapeutic possibilities by targeting mitochondria and mitochormesis to combat inflammatory challenges and infections,” the authors write.
The study was published in the Journal of Clinical Investigation.