Medical genetics

The study find that the Sepsis is a life-threatening condition that occurs when the body’s immune response to infection spirals out of control. Bacteria in the bloodstream trigger immune cells to release powerful molecules called cytokines to quickly activate the body’s defenses. Sometimes the response goes overboard, creating a so-called “cytokine storm” that leaves people feverish or chilled, disoriented and in pain.  Now, researchers at Washington University School of Medicine in St. Louis have found a set of genes that help cells survive exposure to cytokines.

A set of genes

The genes are involved in disposing of cellular waste, a process known as autophagy. Mice that lack key autophagy genes are more likely to die from sepsis, the study shows. The findings raise the possibility that enhancing autophagy could potentially lead to treatments for the deadly condition. When we recognize signs of sepsis in patients; they 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 gene cells; they might be able to promote cell survival and resistance to the cytokine storm, which may ultimately help people survive sepsis.” First author Anthony Orvedahl, MD, PhD, an instructor in pediatric infectious diseases The study is published online the week of  in Proceedings of the National Academy of Sciences.

Pediatric infectious diseases

Sepsis is a medical emergency and even with prompt medical care, about 15% of people do not survive, while many survivors experience longstanding complications.  Orvedahl along with colleagues including senior author Herbert “Skip” Virgin, IV, MD, PhD, now at Vir Biotechnology; and co-author Gary A. Silverman, MD, PhD, the Harriet B. Spoehrer Professor and head of the Department of Pediatrics  set out to find what protects cells from dying during a cytokine storm.

The researchers looked at 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. Further experiments revealed that a second cytokine; called tumor necrosis factor, was also critical for the accelerated cell death in this system.

“Autophagy is like cleaning the house, getting rid of all the junk inside the gene cell,” Orvedahl said. “If unwanted things start to accumulate via a defect in this recycling system, it’s like a tinderbox waiting for a spark. We don’t yet know the exact material involved; but we think something builds up and makes cells more vulnerable to dying when they encounter these inflammatory cytokines.”