The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, has awarded a $10.6 million grant to researchers at the Virginia Bioinformatics Institute and collaborators to determine how the human immune system responds to infection by pathogens of the gut. The funding will be used to apply mathematical modeling to the study of immune responses to gut pathogens.

“The Center for Modeling Immunity to Enteric Pathogens will generate new hypotheses based on computer simulations of the immune responses in the gut and perform pre-clinical and clinical experiments that will reveal how the immune system works when intestinal pathogens invade the human body,” said Josep Bassaganya-Riera, associate professor at the Virginia Bioinformatics Institute, leader of the Nutritional Immunology and Molecular Medicine group in the institute’s CyberInfrastructure Division, and principal investigator of the Center for Modeling Immunity to Enteric Pathogens (MIEP).

“We want to use powerful computer simulations to uncover the mechanisms of action underlying immune responses to intestinal pathogens and accelerate the discovery of drug targets suitable for the prevention and treatment of diseases and disorders caused by gut pathogens, such as persistent diarrhea, gastric cancer, inflammation, and ulcers,” said Bassaganya-Riera.

The MIEP team will work with a wide range of collaborators and engage the infectious disease and immunology communities to disseminate user-friendly mathematical and computational models for the study of human immunity to infection or vaccination.

“Food- and water-borne illnesses that arise from infections with gastrointestinal pathogens cause an enormous health burden around the globe,” said Richard Guerrant, director for the Center of Global Health in the Division of Infectious Diseases and International Health at the University of Virginia School of Medicine. “Escalating medical costs, lost productivity, and premature death are linked to annual outbreaks of pathogens that target the intestinal tract of humans. This project sets out to address the need for more informed scientific research that translates into effective clinical solutions for gastrointestinal infections. It should open novel approaches to providing much needed health solutions to individuals in both developing and industrialized countries.” 

MIEP is organized into four major areas: computational/mathematical model development, immunological experimentation, bioinformatics, and education.

“Generations of life scientists have worked in a reductionist paradigm to provide crucial insight into the interactions between biological systems at scales ranging from organs, tissues, and cells to molecules,” said Stephen Eubank, deputy director of the Network Dynamics and Simulation Science Laboratory at the Virginia Bioinformatics Institute. “What's been lacking is a holistic understanding of how all these pieces function together in a real organism with all its messy irregularity, heterogeneity and complexity across scales.”

Added Madhav Marathe, deputy director of the Network Dynamics and Simulation Science Laboratory at the Virginia Bioinformatics Institute: “Extremely detailed interaction-based modeling is a natural approach to understand these systems. This can only be achieved through high-performance computational modeling and simulation that will stretch the capabilities of even the most powerful machines — a beautiful example of a petascale computing problem. This project is a first step in that direction, with a focused application on enteritis and well-integrated computational and laboratory research teams. An important goal is to allow biologists to use these sophisticated tools without becoming computing experts.”

Bruno Sobral, director of the CyberInfrastructure Division at the Virginia Bioinformatics Institute, commented: “I am delighted to see this project emerge both for the specific biology and infectious disease community that it will serve, but also because of its great strategic cohesion with all of the activities in the CyberInfrastructure Division, as it ties with other crucial projects that we are engaged in such as the Middle Atlantic Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (MARCE), and the PathoSystems Resource Integration Center (PATRIC) efforts. It is because of the integrated biology of host-pathogen-environment interactions that underpins infectious diseases in the real world that these projects also are coordinated through key leaders such as Dr. Bassaganya-Riera. The opportunities within and across projects are substantial, with benefits to all.”

A better understanding of the mechanisms of action underlying immune responses to emerging and re-emerging gut pathogens promises to lead to the development of broad-spectrum vaccines and immunotherapeutics.