Enteric and Diarrheal Disease

Sandhya Visweswariah of the Indian Institute of Science in India will generate a mouse model for studying secretory diarrhea, which causes significant mortality in young children. Secretory diarrhea is often caused by the bacterium Escherichia coli, which produces a toxin that binds to a cell surface receptor (the guanylyl cyclase C receptor) in the gastrointestinal tract thereby causing diarrhea. They will genetically engineer a mouse in which they can hyperactivate this receptor specifically in intestinal cells to potentially trigger secretory diarrhea.

Phillip Tarr of Washington University in the U.S. is developing a method to evaluate gut permeability by measuring levels of ingested fluorescent molecules non-invasively through the skin. Gut permeability is increased in infants with environmental enteropathy, which is associated with impaired growth and development, and is prevalent in developing countries. Current tests are problematic due to the required collection and handling of body fluids from young children, and can produce varying results.

Lijuan Yuan of Virginia Polytechnic Institute and State University in collaboration with Sylvia Becker-Dreps and Andrea Azcarate-Peril from University of North Carolina at Chapel Hill in the U.S. and Samuel Vilchez from University of Nicaragua will develop a pig model with impaired intestinal function and altered types of gut microbes to mimic the condition of many children in developing countries who do not respond to vaccines against rotavirus infection, which causes infectious diarrhea.

Feng Zhang of the Broad Institute of MIT and Harvard in the U.S. proposes to engineer bacterial viruses to deliver enzymes that can be designed to degrade the genome of pathogenic bacteria. These bacteriophages could be used as a new platform for treating drug-resistant bacterial infections.

Mark van Raaij of the Spanish National Research Council (CSIC) at the National Center for Biotechnology in Spain will work to build a library of engineered bacteriophages that can recognize, infect, and kill a range of enterobacteria such as Salmonella and E. coli.

Christopher Voigt of the Massachusetts Institute of Technology in the U.S., along with collaborators Michael Fischbach of the University of California San Francisco and Justin Sonnenburg of Stanford, will engineer a strain of a common bacterial inhabitant of the human gut to contain genetic sensors that can report biomarkers for intestinal disorders in a stool sample.

Garry Blakely of the University of Edinburgh in the United Kingdom will engineer a common gut bacterium to express antigens from pathogens that cause diarrhea onto nanoscale outer membrane vesicles. These nanoparticles could be the basis for a new generation of biocompatible oral vaccines that will protect against diarrheal disease.

Peter Rabinowitz of the University of Washington in the U.S., along with colleagues at Washington State University and CDC Kenya, will test whether unhealthy gut microbes in livestock that co-reside with humans in smallholder households can negatively influence the gut microbes in the humans, and whether this can be exploited to improve human health. The microbial community (microbiota) living in the gut is important for childhood health, growth and development.

Marie Lewis of the University of Reading in the United Kingdom will establish pig models of environmental enteric dysfunction (EED) and acute secretory diarrhea (ASD) to develop and test new therapeutic approaches. Rodents are commonly used to model human enteropathies, but their physiology is quite different and often therapies that work in rodents fail in humans. Pigs may be a more valuable disease model as their biology is more comparable to humans.

Mark Donowitz and Nicholas Zachos of Johns Hopkins University in the U.S. will develop human epithelial cell cultures that mimic the human intestine as a model for acute diarrhea, which is the second leading cause of death worldwide. They will culture the cells as polarized monolayers, which can be infected with disease- causing pathogens, and use them to measure the effect on NaCl absorption, which is blocked in almost all diarrheal diseases. They will also upgrade their model to mimic the mechanical forces experienced by the human intestine during the passage of food.