Acute respiratory distress syndrome (ARDS), which can ultimately result in death in the elderly or the fragile, is brought on by many respiratory infections, including influenza or COVID-19, which put a great deal of stress on cells and organs. To keep a check of our upper respiratory tract disorder, we should regularly visit our General Physician.
According to Professor Johan Auwerx at the School of Life Sciences at EPFL, “novel therapeutic strategies to address ARDS could try to elicit the host organism’s tolerance towards the inflammatory challenge by boosting its natural adaptive stress responses.”
In a recent study, Adrienne Mottis from EPFL and her coworkers demonstrated how one tactic can take advantage of a biological phenomenon called “mitohormesis.” Mild stress on a cell’s mitochondria can result in a cascade of reactions that improve the cell’s health and viability, a process known as mitohormesis. The primary energy-harvesting organelles of the cell, mitochondria, are constantly being watched by the cell’s “surveillance” systems.
This ongoing quality control can trigger adaptive compensatory reactions referred to as “mitochondrial stress responses” if the mitochondria malfunction or are under stress.
Since the positive effects of these stress responses can outweigh the harmful effects of the initial stressor, a mild level of mitochondrial stress may therefore be advantageous for the cell and the organism, according to study leader Mottis. This theory is supported by earlier research that demonstrates how inducing mitohormesis can lengthen lifespan by reducing the effects of aging or metabolic disorders.
Because mitochondria are descended from bacteria, antibiotics can be used on them. To combat various infections, including acne, cholera, plague, malaria, and syphilis, the researchers examined multiple antibiotics that could stress mitochondria and discovered novel molecules in the tetracycline family. Tetracyclines are a class of antibiotics that blocks the synthesis of mitochondrial proteins.
The researchers screened fifty-two tetracyclines and chose novel molecules like 9-test-buy doxycycline (9-TB) because they are highly effective at inducing mitohormesis even at low doses and have no antibiotic effect, meaning they do not affect the host’s microbiome. When tested on mice, the compounds led to mild mitochondrial stress and advantageous mitohormetic responses, increasing the mice’s tolerance to influenza virus infection.
“Most importantly, our study demonstrates that the 9-TB-triggered mitochondrial responses mobilize signaling pathways of innate immunity, the so-called type I interferon response, and activate the ATF4 signaling pathway, a well-described response to multiple cellular stressors,” continues Auwerx. “As a result, while not affecting the viral load, 9-TB increased the survival of mice exposed to lethal influenza infection. While tolerance refers to the mechanisms that restrict the degree of organ dysfunction and tissue damage brought on by infection, it does not necessarily impact pathogen load; resistant hosts fight infection by inducing an immune response that lowers the pathogen load.”
The research demonstrates that 9-TB, without affecting the microbiome, can help mice develop a tolerance to influenza infection by lessening the degree of tissue damage and inflammation. The authors write, “These results open novel therapeutic avenues by targeting mitochondria and mitohormesis to combat inflammatory challenges and infections.”