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Potential Drug Target May Curb Hospital-Acquired Infection

Researchers focus on intestinal C. difficile (Nov. 30)

Researchers at the Virginia Bioinformatics Institute in Blacksburg, Va., have discovered how a common diarrhea-causing bacterium sends the body’s natural defenses into overdrive, intensifying the illness while fighting infection. The discovery, published in PLoS One, may lead to new drug treatments for Clostridium difficile –– a germ commonly involved in healthcare-associated infections. Infection with C. difficile kills 14,000 Americans annually, according to the Centers for Disease Control and Prevention.

Researchers used computational and mathematical modeling in combination with RNA sequencing and mouse studies to understand an important regulatory pathway during C. difficile infection. They found that tissue damage and disease severity in this setting is associated with disruption of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) pathway.

The human intestine must coexist with trillions of beneficial bacteria while swiftly responding to pathogens such as C. difficile. Sometimes the immune system will go into overdrive when responding to pathogens, causing more damage in an attempt to clear the infection.

Scientists studying the bowels of mice found that the PPAR-gamma pathway keeps the immune response in check, allowing the body to heal while the immune cells that fight infection do their work in a controlled manner. When PPAR-gamma was absent or inactive, disease was more rampant, and colonic lesions from C. difficile infection were much worse.

In addition, the researchers found that the protective mechanism can be activated and the severity of the C. difficile infection can be reduced by using an existing diabetes drug. More studies will be needed before the drug can be tested against C. difficile, however.

“With continued research, new drugs targeting this pathway will be developed that will have fewer side effects and greater efficacy than those currently on the market,” said principal investigator Dr. Joseph Bassaganya-Riera.

C. difficile has become a widespread problem in hospitals with patients who have received heavy doses of multiple antibiotics, and it is spreading in the community, the researchers say. Symptoms of infection include persistent diarrhea, fever, gut inflammation, and weight loss. Even though such potentially life-threatening intestinal infections occur among very young, elderly, or immune-compromised individuals, C. difficile has increasingly been found in patients who traditionally would not be susceptible to the bacterium.

According to the researchers, current strains of C. difficile have become even more virulent and resistant to antimicrobial drugs in recent years, and this development emphasizes the importance of discovering broad-based, host-targeted approaches to control the disease as opposed to relying on antimicrobial therapies that target the bacterium and potentially stimulate the spread of resistance.

Source: Virginia Polytechnic Institute; November 30, 2012.

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