Research on Clostridium difficile infection yields promising new drug target

BLACKSBURG, Va., October 17, 2012 – Researchers in the Nutritional Immunology and Molecular Medicine Laboratory at Virginia Bioinformatics Institute have reported new findings that suggest a different host-targeted approach for treating the infectious diarrhea-causing bacterium, Clostridium difficile. The paper was published in PLOS One.

“The Center for Modeling Immunity to Enteric Pathogens at Virginia Tech has applied computational and mathematical modeling approaches in combination with RNA-sequencing and mouse challenge studies to characterize the disruption of an important regulatory pathway during Clostridium difficile infection. 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 Josep Bassaganya-Riera, professor of immunology at Virginia Tech, director of the Nutritional Immunology and Molecular Medicine Laboratory and the PI of the Center for Modeling Immunity to Enteric Pathogens.

The human intestine must peacefully 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. Activation of PPARγ by using a diabetes drug ameliorated C. difficile-related gut pathology and disease in mouse challenge studies. Thus, PPARγ helps keep the immune response in check, allowing the body to heal but also allowing the immune cells that fight infection to do their work in a controlled manner. When PPARγ was absent or not activated, disease was more rampant and colonic lesions from C. difficile were much worse.

“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.

This research builds on previous work from the Nutritional Immunology and Molecular Medicine Laboratory, which shows that PPARγ is critical to reducing disease caused by enteric pathogens and regulating autoimmune diseases such as inflammatory bowel disease.

“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 Professor 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. Symptoms 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 this bacterium. Current strains of C. difficile have become even more virulent and anti-microbial resistant in recent years which emphasizes 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.

Please visit the MIEP Web Portal at http://www.modelingimmunity.org/.

MIEP is funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, under Contract No. HHSN272201000056C. PI: Josep Bassaganya-Riera.

About NIMML

The NIMML Institute is a 501 (c) (3) non-profit public charity foundation focused on a transdisciplinary, team-science approach to precision medicine at the interface of immunology, inflammation, and metabolism. The NIMML Institute team has led numerous large-scale transdisciplinary projects and is dedicated to solving important societal problems by combining the expertise of immunologists, computational biologists, toxicologists, modelers, translational researchers, and molecular biologists. The Institute is headquartered in Blacksburg, VA. For more information, please visit www.nimml.org or contact [email protected].