Enteric and Diarrheal Disease

Kevin Esvelt of President and Fellows of Harvard College in the U.S. will use CRISPR technology to make protective healthy bacteria resistant to phage so they can outcompete pathogenic bacteria that cause childhood diarrhea and stunting. He will develop a method to make the protective Nissle 1917 strain of E. coli resistant to a range of phage, and use it to replace native E. coli strains in the guts of young mice as a model for human infants. This approach will provide long-term protection against pathogenic bacterial infections at low cost.

Chase Beisel of North Carolina State University in the U.S. will exploit non-lytic bacteriophage for promoting infant gut health and treating enteric infections in low-resource settings. Generally, lytic phage are being studied for treating diseases, but they suffer from a number of limitations including causing resistance and the release of endotoxins, which can damage healthy cells.

Paul Barrow of the University of Nottingham in the United Kingdom will identify bacteriophage (viruses that infect bacteria) that can reduce the presence of multiple pathogenic bacteria in the gut to restore healthy bacterial populations (microbiome) and help treat diarrheal diseases. They will characterize phage specificity for three major pathogens that infect both humans and pigs, and select those that are less likely to cause the development of resistance.

Samuel Alcaine of the University of Massachusetts Amherst in the U.S. will engineer bacteriophage (viruses that infect bacteria) to produce an antimicrobial compound that helps avoid bacteria such as enteroaggregative Escherichia coli developing resistance to the phage, thereby increasing their value for treating associated childhood diseases. Phage could be valuable for treating intestinal diseases that cause severe morbidity and mortality in developing countries as they can selectively destroy pathogenic bacteria.

David Wang of Washington University in St. Louis in the U.S. will evaluate specific RNA bacteriophage (viruses that infect bacteria) as therapeutics to modulate the bacterial communities in inflammatory conditions such as environmental enteropathy. To date, only DNA phage have been explored as therapeutics despite RNA phage being able to kill a broader range of bacteria. They will test the effect of two prototypical RNA phage on the gut microbe population in a mouse model of intestinal inflammation.

Baojun Wang of the University of Edinburgh in the United Kingdom will engineer bacteriophages to selectively target gut pathogens such as Shigella and Salmonella that cause widespread environmental enteropathy in infants in developing countries. They will program the CRISPR-Cas9 (clustered, regularly interspaced short palindromic repeats-CRISPR-associated proteins) nucleases to cut the chromosomes of the target pathogens, and test their ability to block infection in a mouse gut colonization model while leaving the non-pathogenic and often beneficial bacteria largely intact.

Bryan Hsu from Harvard Medical School in the U.S. will develop a mouse model carrying specific bacteria to mimic conditions in the infant gut for studying bacteria-infecting viruses known as phage, which could be valuable agents for treating infectious diseases and promoting child health in developing countries. Understanding how phage behave within the complex human gut is a critical step towards developing phage-based therapeutics that can safely modify resident bacterial populations.

Jennifer Mahony and Douwe van Sinderen of University College Cork in Ireland, with Marco Ventura of University of Parma in Italy, will study how bacteriophage, which are viruses that infect and kill bacteria, affect both beneficial and pathogenic bacterial populations over time in the guts of infants from developing countries, which ultimately influence infant health and well-being.

Reza Nokhbeh from the Advanced Medical Research Institute of Canada in Canada will genetically engineer phage that infect pathogenic Escherichia coli bacteria to express proteins and short RNA molecules that block multiple bacterial functions and thereby stop it from colonizing the human gut and causing disease. Diarrheal diseases cause substantial mortality in children under five in developing countries, and there is an urgent need for new treatments. They will develop their approach to first target E.

Diane Joseph-McCarthy of EnBiotix Inc. in the U.S. will use a systems biology approach incorporating gene, protein and metabolic data to computationally model the complex interplay between specific microbes in the gut and the host response, and the effect of phage, to enhance our understanding of pathogenic diseases and identify new treatments. They will use a mouse model of enteropathogenic E.