Enteric and Diarrheal Disease

Martin Blaser of the New York University School of Medicine in the U.S. proposes to engineer a harmless modification of H. pylori, a bacteria commonly found in the human stomach, to deliver antigens to protect against intestinal pathogens such as cholera and campylobacter. This modified H. pylori can only survive in the presence of an enzyme supplied in special drinking water, allowing those administering the vaccine to regulate its colonization.

Egil Lien with collaborators Beth McCormick and Mike Brehm of the University of Massachusetts Medical School in the U.S. will evaluate two mouse models for studying human typhoid fever. Typhoid fever is a major cause of environmental enteric dysfunction, which is associated with significant morbidity and mortality particularly in young children from developing countries. The causative Salmonella bacterium does not normally infect mice, hindering the development of mouse models for testing new treatments and vaccines.

Cirle Warren of the University of Virginia in the U.S. will develop a three dimensional cell culture model (organoid) of the human intestine to study diarrheal diseases. They will build the organoids in a bioreactor using three intestinal cell types, and test different scaffolds to simulate the complex cellular and structural architecture of the human gut. The organoids will then be infected with Cryptosporidium, a common cause of diarrhea in developing countries, and analyzed for altered structural and molecular characteristics to gain insight into the host infection response.

James Nataro of the University of Virginia in the U.S. is developing new mouse models of environmental enteric dysfunction (EED) to explore how enteric pathogens commonly found among children in developing countries can affect intestinal function and cause growth retardation. In Phase I, they developed mouse models for five of the common pathogens and found that, as in humans, malnutrition (protein or zinc deficiency) enhanced the severity of infection, associated growth retardation, or the presence of intestinal inflammation.

Haiqing Sheng and collaborators Carolyn Bohach and Scott Minnich from the University of Idaho in the U.S. will exploit the CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9) system in a dual approach to combat enteropathogenic Escherichia coli (EPEC) infections. EPEC cause diarrhea and result in several hundred thousand infant deaths annually.

Corinne Maurice of McGill University in Canada will use an ecological approach to determine whether bacteriophage (phage), which are viruses that infect bacteria, could be used to restore healthy microbial communities in the gut and thereby reduce stunting in children. They will collect stool samples from infants under two years old from Bangladesh, and compare the types of phage and bacteria found in stunted versus healthy children.

Anika Kinkhabwala of EpiBiome in the U.S. will exploit the development of resistance to bacteriophage by pathogenic bacteria to improve children's gut health. Bacteriophage recognize proteins and other molecules found on the surface of bacteria, which they use to infect and kill them. They will identify bacteriophage isolated from fecal and sewage samples that can target virulence structures on the surface of the pathogenic bacteria enterotoxigenic Escherichia coli (ETEC) and Shigella dysenteriae, which are common diarrhea-causing bacteria.

Lori Holtz of Washington University in the U.S. will analyze the composition of bacteriophage (viruses that infect bacteria) in the gut of young children to see if it is linked with the chronic inflammatory gut condition, environmental enteropathy, which is highly prevalent in low-income countries and is linked to malnutrition and stunted growth. They will perform metagenomic sequencing on available fecal samples taken over a 6-month period from 489 children under age two from Malawi who were tested for gut dysfunction.

Jason Gill of Texas A&M AgriLife Research in the U.S. will develop an animal model for environmental enteropathy, which is a chronic inflammatory condition of the gut prevalent in children from low-income countries, to test new bacteriophage-based treatments. Bacteriophage (phage) are viruses that infect and can kill bacteria, and can therefore be used to treat bacterial diseases. They will develop a chronic disease model by infecting weaned piglets with low doses of enterotoxigenic Escherichia coli, which is likely involved in environmental enteropathy development in humans.

Alessio Fasano of Massachusetts General Hospital in the U.S. will isolate bacteriophage (viruses that infect bacteria) that specifically kill pathogenic Escherichia coli and Shigella bacteria, which cause environmental enteropathy and other potentially deadly childhood diseases. They will perform a high-throughput screen using a diverse phage library to isolate phage that specifically target the type-III secretion system expressed by enteric pathogens like E. coli.