have discovered how Clostridium difficile, a common germ in healthcare-associated infections, sends the body's
natural defenses into overdrive, actually intensifying illness while fighting
The discovery at Virginia Bioinformatics Institute at Virginia Tech
in the US, which was recently published in PLOS One, may lead to new drug
treatments for C. difficile. The bacterium has been linked to the death of 14,000 Americans
annually, according to the Centers for Disease Control and Prevention.
Researchers with the Center for Modeling Immunity to Enteric
Pathogens at Virginia Tech applied computational and mathematical modeling in
combination with RNA-sequencing and mouse studies to understand an important regulatory
pathway during C. difficile infection.
The human intestine must
peacefully coexist with trillions of beneficial bacteria while quickly
responding to pathogens such as C.
difficile. Sometimes the immune system will go into
overdrive when responding to such pathogens and in the attempt to clear
infection more damage is caused. "We have found that tissue damage and disease
severity in C. difficile infection is associated with a disruption of the peroxisome
proliferator-activated receptor gamma (PPARγ) pathway," said Professor Josep Bassaganya- Riera, director of
the Nutritional Immunology and Molecular Medicine Laboratory, and the principal
investigator with the Center for Modeling Immunity to Enteric Pathogens.
When studying the bowels of mice, researchers found that the PPARγ 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 PPARγ was absent or inactive, disease was more rampant and colonic lesions from C. difficile were much
In addition, researchers found that by using an existing diabetes
drug the protective mechanism could be activated and the severity of the C. Difficile infection
could be reduced. More studies will be needed before the drug can be tested
against C. difficile.
"This research demonstrates that the integration of powerful
computer simulations of host responses with immunology experimentation not only
contributes to a better understanding of the immunoregulatory processes in the
gut mucosa during C. difficile infection, but it also advances the discovery of broad-based therapeutic
targets in the host for infectious diseases," said Raquel Hontecillas,
assistant professor of immunology at Virginia Tech, co-director of the Nutritional
Immunology and Molecular Medicine Laboratory and leader of the immunology
component of the Center for Modeling Immunity to Enteric Pathogens.
C. difficile has become a widespread problem in hospitals, particularly with patients who have received heavy doses of multiple antibiotics, and the problem continues to spread in the community, increasingly being found in patients who traditionally would not be susceptible to this bacterium. Symptoms include persistent diarrhea, fever, gut inflammation, and weight loss.
Current strains of C. difficile have become even more virulent and antimicrobial resistant in recent years, which emphasises the importance of developing broad-based, host-targeted approaches to control the disease as opposed to just relying on anti-microbial therapies that target the bacterium and can stimulate the spread of resistance.