NEW YORK, Nov. 14, 2006. According to a new study, septic shock--a dangerous, often deadly runaway immune response--is controlled by a genetic on/off switch. The research also suggests how a drug might temper sepsis. This is the first time this genetic mechanism has been revealed in an experimental animal.
The study by Robert Schneider, Ph.D., the Albert B. Sabin Professor of Microbiology and Molecular Pathogenesis at NYU School of Medicine and his colleagues, is being published in the November 15th print edition of the journal Genes & Development
A killer and a protector
Septic shock is the nation's 10th most frequent cause of death and the leading cause of hospital-related mortality. Bacterial infection, notably the toxins that are part of the bacterial cell wall, stimulate the inflammatory response which can spin out of control. Sepsis progresses swiftly from chills, fever and shallow breathing, to dilated and leaky blood vessels, a lack of blood supply in the body's organs, multiple organ failure and, often, death.
Infection causes the body's immune system to produce protective proteins called cytokines. Problems arise when the body is unable to turn off cytokine production and they overwhelm the body, says Dr. Schneider. "The resulting cytokine storm is, for example, what kills people when they are infected with anthrax and, we think, an important factor in what killed people in the flu pandemic of 1918," he says.
Dr. Schneider and his colleagues focused on one of the key genes that regulate cytokine production called auf1, which has been extensively studied in tissue culture but not in animals. In an attempt to move the research closer to the clinical setting, the team genetically engineered and bred mice lacking the auf1 gene, a so-called knock-out mouse. Then, mice with the gene and mice without it were exposed to a bacterial toxin that causes mild food poisoning. The normal mice had little problem fending off the endotoxin. "The mice without the gene died due to an uncontrolled septic-shock like response--their blood vessels burst, their spleens were destroyed," says Dr. Schneider. Mortality was five-fold higher in mice without the auf1 gene.
Further research showed where auf1 functions at the molecular level, he says. In normal mice, the scientists found that auf1 steps into action once the immune response is activated and after cytokine production gets underway. The action is pronounced: messenger RNAs (mRNAs) which are blueprints for very specific cytokines--namely interleukin-1 beta, tumor necrosis factor alpha and COX-2--are degraded. That process of degrading the mRNAs shuts off production of these cytokines.
In the study, mice lacking the auf1 gene do not seem to have that off switch; their cytokine levels were greatly elevated. A cytokine storm had caused sepsis in these animals.
In summary, auf1 is a protector that can stop an infection from progressing to septic shock, explains Dr. Schneider. It does so by helping with cytokine production and then tempering the production of these proteins. Auf1 acts like a cytokine on/off switch.
The future possibilities
Dr. Schneider believes auf1 makes an excellent target for the development of therapeutics. For example, a drug could turn on auf1 or stabilize its activity as a way to specifically tone down production of those cytokines that are the major players in sepsis, he says. His study results might also help explain why many previous sepsis drug trials have failed. The cytokine storm needs to be turned off at its source, he says, and auf1 offers the on/off switch to do just that.
The paper was authored by Dr. Schneider along with Navid Sadri, an M.D./Ph.D. student in his lab and former student Jin-Yu Lin, Ph.D., who is currently a post-doctoral fellow at Yale University School of Medicine.
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