Awards

Linda Saif from Ohio State University in the U.S. will develop a pig model to recapitulate the vicious cycle of malnutrition and repeated enteric infections seen in young children in developing countries in order to study the underlying biology and identify effective treatments. Childhood malnutrition is rife in impoverished regions, and causes substantial mortality and disabilities. It impairs gut function and immunity, and leads to increased enteric infection rates. They will explore the relationship between malnutrition and enteric infections using piglet models of malnutrition and multiple pathogen-associated enteropathy, and analyze the effects on the cellular and microbial composition of the gut, and the immune response. They will also test whether specific diets and supplements such as tryptophan can restore healthy gut function.

Carson Meredith from Georgia Tech in the U.S. will determine whether pollen can measure gut function by assessing mucus qualities, which vary along the gastrointestinal tract particularly in children with enteric diseases. Gastrointestinal mucus prevents pathogens entering the body and promotes the absorption of nutrients and medicines. Therefore, its physical properties are relevant for gut health and the development of effective treatments. Pollen particles vary widely in size and shape, and can survive the harsh environment of the gastrointestinal tract. He will test the ability of a selection of pollen to probe properties such as water content and viscosity of synthetic and porcine intestinal mucus using an established technique known as particle tracking microrheology to track pollen motion.

Marcela Pasetti of the University of Maryland in the U.S. will generate an in vitro model of the gut using intestinal stem cells and immune cells to better mimic the damaged and inflamed guts of young children in developing countries for testing new treatments. Current so-called human enteroid models lack additional relevant cell types found in the intestine, particularly immune cells, which are known to play an important role in gut health and function. They will expose their new miniature pediatric gut model to enteric pathogens and test the ability of human breast milk and bovine hyperimmune colostrum to repair the subsequent damage.

Cirle Warren from the University of Virginia in the U.S. will develop a mouse model with an intestinal tract that is primed to mimic the human intestine in order to better study enteric infections and identify effective treatments. Several environmental enteropathies cannot be studied in the mouse because they do not simulate the human physiological response. To address this, they will test different conditions for transplanting feces from healthy children into pregnant mice to transfer human gut microbes and promote the development of a 'humanized' gut in the unborn mice. These mice will then be challenged with a specific intestinal infection and analyzed for similarities to the human response, including changes to gut physiology and immune responses.

Ralph Tripp from the University of Georgia in the U.S. and Carl Kirkwood of Murdoch Children's Research Institute in Australia will engineer mammalian cell lines for the development of vaccines and therapies against human noravirus and related enteric viruses. Noravirus is highly contagious and causes acute gastroenteritis, which can be serious in young children and the elderly. However, studying the virus and developing much needed new therapies has been difficult because mammalian cells are unable to support replication of the virus and grow in culture. They will perform genome-wide screens on two mammalian cell lines using small interfering RNA libraries to identify and remove the genes that block viral replication. After validation, the candidate genes will be modified using so-called CRISPR gene editing to generate stable cell lines for studying viral biology and developing new treatments.

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. The effect on the gastrointestinal tract and any accompanying molecular changes will then be analyzed and could lead to the discovery of new therapeutic targets.

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. They will implant stools from vaccine-responsive and non-responsive children in Nicaragua into the pigs and use them to identify factors that improve vaccine-mediated immune responses. This model can also be used to test disease prevention strategies, such as feeding probiotics or special diets.

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. In contrast, this new method would allow direct measurement in the field, and be suitable for resource-poor settings. In Phase I, they showed that orally ingested pyrazine-based fluorophores could be measured through the skin and could detect gut injury in a rat model of enteropathy. In Phase II, they will optimize the fluorophores to improve solubility, and evaluate them in a preliminary trial in human volunteers.

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. However mice lacking the innate immune receptor toll-like receptor 11 (TLR11) and humanized NOD-SID-IL-2Rg (NSG) mice can be infected. They will analyze the characteristics of typhoid fever in these two mouse models and the effect of current treatments.

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. This model could also be used to identify new drug targets and evaluate candidate drugs.