Lack of a key enzyme dramatically increases resistance to sepsisApril 24, 2006
According to the new study, the presence of caspase-12, which appears to modulate inflammation and innate immunity in humans, increases the body's "vulnerability to bacterial infection and septic shock" while a deficiency confers strong resistance to sepsis. This new discovery suggests that caspase-12 antagonists could be a potentially useful in the treatment of sepsis and other inflammatory and immune disorders.
The study was published in the April 20 edition of the journal Nature (Volume 440, Number 7087).
Richard Ulevitch, chair of the Scripps Research Immunology Department and an author of the paper, says, "The results of the study make clear that caspase-12 plays a critical role in the elimination of bacterial pathogens, and that a deficiency allows systemic and abdominal infections to be better resolved. It's known that the presence of caspase-12 as a full length protein occurs in a small percentage of people of African descent. As a result, some of these individuals are far more susceptible to severe sepsis and have a significantly increased risk of dying from it."
Sepsis, the body's inflammatory response to severe infection, is one of the leading causes of death in the United States, killing more than 200,000 people each year, according to the Society of Critical Care Medicine. A 2003 study by The Centers for Disease Control and Emory University School of Medicine showed that the incidence of sepsis in the United States has increased almost nine percent a year since 1979.
The new study showed that caspase-12 deficient mice were resistant to peritonitis and septic shock and were able to clear pathogenic bacteria more efficiently than mice with the enzyme. The presence of caspase-12 also reduced production of several pro-inflammatory cytokines, increasing vulnerability to bacterial infection and septic mortality.
"Without the experimental model of peritonitis perfected by John Mathison from Scripps Research, we would not have been able to differentiate between the two mouse phenotypes," Ulevitch said. "Because of his work, we were able to use a surgically implanted stent in the colon that allowed a gradual occurrence of sepsis and easy identification."
A majority of mice with caspace-12 died from sepsis within the first 48 hours after onset, while 60 percent of the caspase-12 deficient mice survived. The deficient mice also showed a significantly lower number of bacterial colony-forming units per milliliter of blood, suggesting that more efficient bacterial clearance occurs in the absence of caspase-12.
Caspase-12 is also an inhibitor of caspase-1, a related enzyme involved in the inflammation process. Caspase-1 deficient mice are two-to-three times more susceptible to lethal Escherichia coli infection than normal mice. Consequently, the study said, sepsis resistance in caspase-12 deficient mice was most likely due to an initial hyper-production of cytokines that fight the infection.
"The resulting beneficial effect of cytokine hyper-production runs contrary to some of the current thinking in sepsis research," Ulevitch said. "The general thinking is that this initial cytokine 'storm' is harmful, and that belief has been the basis of a number of unsuccessful clinical studies. In our study, cells containing caspase-12 appear to weaken the activity of caspase-1 that is normally essential for bacterial clearance and sepsis survival."
In another finding, researchers showed that both mouse models had similar levels of stress-induced apoptosis or programmed cell death. While caspase-12 was previously thought to be a key mediator of endoplasmic reticulum apoptosis, the new study found that the presence or absence of caspase-12 had no effect on apoptotic sensitivity whatsoever.
Others authors of the study include Maya Saleh (currently with McGill University), Melissa K. Wolinski, Steve J. Bensinger, Patrick Fitzgerald, Nathalie Droin, Douglas R. Green (La Jolla Institute of Allergy and Immunology and St. Jude Children's Research Hospital); Donald W. Nicholson of Merck Research Laboratories, and; John C. Mathison of Scripps Research.
Scripps Research Institute
Related Sepsis Current Events and Sepsis News Articles
World's first bilateral hand transplant on child at Children's Hospital of Philadelphia
Surgeons at The Children's Hospital of Philadelphia (CHOP) joined with colleagues from Penn Medicine recently to complete the world's first bilateral hand transplant on a child.
Extreme exercise linked to blood poisoning
Researchers have discovered that extreme exercise can cause intestinal bacteria to leak into the bloodstream, leading to blood poisoning.
New microscope technique could speed identification of deadly bacteria
A new way of rapidly identifying bacteria, which requires a slight modification to a simple microscope, may change the way doctors approach treatment for patients who develop potentially deadly infections and may also help the food industry screen against contamination with harmful pathogens, according to researchers at the Korea Advanced Institute of Science and Technology (KAIST) in Daejeon, South Korea.
Scientists discover bacterial cause behind fatal heart complications
Streptococcus pneumoniae is a major human pathogen and is known to be associated with increased risk of fatal heart complications including heart failure and heart attacks.
Single low-magnitude electric pulse successfully fights inflammation
The Feinstein Institute for Medical Research, the research arm of the North Shore-LIJ Health System, and SetPoint Medical Inc., a biomedical technology company, today released the results of research on the therapeutic potential of vagus nerve stimulation.
Stanford scientists find genetic signature enabling early, accurate sepsis diagnosis
Investigators at the Stanford University School of Medicine have identified a pattern of gene activity that could help scientists create a blood test for quickly and accurately detecting whether patients are experiencing a deadly immune-system panic attack.
In late post-surgical colon 'leaks,' finger points to microbes
Post-surgical leaks that develop after a segment of the colon has been removed and stitched back together often are caused not by negligence or technical error but by bacteria in the bowel that elude antibiotics, according to new evidence about this devastating complication of gastrointestinal surgery.
New care approach to colorectal operations speeds patients' recovery times
Patients undergoing colorectal operations who participated in an enhanced recovery program left the hospital sooner and had significantly lower hospital costs than patients who had the traditional approach to their care, according to a new study, which also found further postoperative improvements after adding an infection prevention protocol.
Cirrhosis deaths drop 41 percent from 2002 to 2012
A new study by UNC researchers has found dramatic improvements in the survival of patients with cirrhosis and liver failure supporting improved treatment strategies for patients with cirrhosis and concurrent bacterial infections.
Study examines long-term adverse health effects of Ebola survivors
Ebola survivors experienced negative health effects that persisted more than two years after the 2007-2008 Bundibugyo ebolavirus (BDBV) outbreak in Uganda that claimed 39 lives.
More Sepsis Current Events and Sepsis News Articles