BLACKSBURG, Va., July 25, 2014 – A collaborative team of scientists from Virginia Bioinformatics Institute and Vanderbilt University has made steps toward understanding the immune response involved in Helicobacter pylori infection. Using a combined computational and experimental approach, they demonstrate how the cytokine interleukin-21 (IL-21) may play a key role in immune responses to H. pylori infection.  The study is published in the July issue of MBio.

“Applying systems computer modeling allows us to predict which signaling pathways and T cell responses are impacted by IL-21. With this greater understanding, we can refine and better focus our experimental efforts,” said Holly Algood, assistant professor at Vanderbilt University and a lead researcher on the study.   

H. pylori naturally infects the gastrointestinal tract of approximately half the world’s population. The bacterium has been implicated in numerous gastric diseases, including ulcers, gastritis, and gastric cancer. However, many studies have suggested that H. pylori also plays a beneficial role, protecting against childhood allergies, childhood asthma, obesity, and diabetes. Although doctors currently use antibiotics to treat H. pylori-caused disease, some scientists argue that eradicating the bacterium might not be the best therapeutic option. In addition, over-use of antibiotics may result in development of antibiotic resistance, making the bacteria more difficult to treat.

IL-21 plays a critical role in immune responses to infection. It is produced by a variety of immune cells and has anti-tumor and anti-viral properties. But it also leads to excessive inflammation. Often, the immune and inflammatory responses  triggered by the bacteria are far worse than the infection itself, and it is these responses that lead to pathology and disease.

“Although IL-21 is helpful in many ways, in the case of H. pylori infections, it can exacerbate damage to the stomach. Computational modeling has helped us determine how the IL-21 pathway affects inflammation, and this will lead to the development of better therapies,” said Adria Carbo, first author of the study.

MIEP researchers are using computational simulations to find innovative ways to modulate the IL-21 response. This work helps them better understand the role of IL-21 in H. pylori-related pathology and devise ways to develop more targeted therapies for H. pylori infection that target the host rather than the bacterium.

“The computational models we’ve developed have greatly increased understanding of the role of IL-21 in modulating immune responses to pathogens. For instance, the modulation of IL-10 production in CD4+ T cells by IL-21 was a non-intuitive finding predicted in our simulations and validated experimentally. We can now move toward development of IL-21-based host targeted therapeutics against infectious and immune-mediated diseases,” said Raquel Hontecillas, co-director and Immunology Lead of the Center for Modeling Immunity to Enteric Pathogens (MIEP).

Previous work from MIEP focused on creating computational models that have helped researchers better understand the dual role of H. pylori as a pathogen and a beneficial member of the gastric microbiota.

“The collaboration between Vanderbilt and Virginia Tech opens new possibilities for understanding the pathology of H. pylori infection,” said Josep Bassaganya-Riera, director of MIEP. “Building on the foundation of computational models developed by MIEP, our team effort allows us to gain vital new knowledge about mechanisms of action as well as translation of our computational modeling and bioinformatics innovations to the clinic.”

The Center for Modeling Immunity to Enteric Pathogens is funded through the National Institute of Allergy and Infectious Diseases of the National Institutes of Health contract number HHSN272201000056C. 

The Nutritional Immunology and Molecular Medicine Laboratory (NIMML) conducts translational research aimed at developing novel therapeutic and prophylactic approaches for modulating immune and inflammatory responses. The Laboratory has over 20 researchers and combines computational modeling, bioinformatics approaches, pre-clinical experimentation, and human clinical studies to better understand the mechanisms of immune regulation at mucosal surfaces and ultimately accelerate the development of novel treatments for infectious and immune-mediated diseases. In addition, the NIMML team leads the NIAID-funded Center for Modeling Immunity to Enteric Pathogens (MIEP).

August 21, 2014