Researchers from Washington School Of Medicine in St Louis have identified a set of genes involved in disposing cellular waste through a process known as autophagy that helps cells survive exposure to cytokines during sepsis.
Sepsis is a life-threatening condition that occurs when the body's immune response to infection spirals out of control. Bacteria or other pathogens in the bloodstream trigger immune cells to release powerful molecules called cytokines to quickly activate the body's defenses. In sepsis, this response goes overboard, creating a so-called "cytokine storm" that leaves patients feverish or chilled, disoriented and in pain. In chronic cases, it can lead to multi-organ failure and death. Sepsis is a medical emergency and even with prompt medical care, about 16 percent of people do not survive, while many survivors experience longstanding complications and bodily damages.
The researchers using animal models discovered that specimens that lacked key autophagy genes are most likely to die from sepsis. The findings raise the possibility that enhancing autophagy could potentially lead to treatments for the deadly condition.
Dr Anthony Orvedahl, lead author commented in a phone interview with Thailand Medical News, "When we recognize signs of sepsis in patients, we prescribe antibiotics and fluids, but we lack therapies to protect patients from the direct effects of the cytokine storm. Our research indicates that if we could modulate autophagy levels in cells, we might be able to promote cell survival and resistance to the cytokine storm, which may ultimately help people survive sepsis."
The team studied the effects of interferon gamma, a cytokine that activates immune cells' ability to kill bacteria but can also trigger cell death. By systematically inactivating one gene at a time from immune cells in a dish before treating them with interferon gamma, the researchers discovered that cells need a full complement of autophagy genes to survive exposure to the potent cytokine.
Additional studies revealed that a second cytokine, called tumor necrosis factor, was also critical for the accelerated cell death in this system.
Dr Anthony further added,"Autophagy is like cleaning the house, getting rid of all the junk inside the cell. If unwanted things start to accumulate via a defect in this recycling system, it is like a box of explosives waiting for a spark. “
Chemical compounds that enhance or block autophagy are already being studied by researchers focused on cancer, cardiovascular disease and other conditions. Therapies that suppress autophagy may increase the risk of sepsis. More research is needed before doctors can evaluate whether boosting autophagy is a viable strategy for treating sepsis.
Reference : Anthony Orvedahl el al., "Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock," PNAS (2019). www.pnas.org/cgi/doi/10.1073/pnas.1822157116