Enteric and Diarrheal Disease

Jan Mead of Emory University in the U.S. will develop a mouse model of cryptosporidiosis using human fecal transplants to mimic changes in the bacterial populations (microbiome) in the gut that occur in the human disease, which causes substantial morbidity and mortality in young children from developing countries. Drugs used to eradicate the intestinal parasite Cryptosporidium are thought to be affected by the levels and types of bacteria that populate the human gut, which is of particular importance in malnourished children who most often become infected.

Olga Tosas Auguet of the University of Oxford and collaborators at the Modernising Medical Microbiology Consortium, Guy's and St Thomas' NHS Foundation Trust, Oxford Genomics Centre and London School of Hygiene and Tropical Medicine in the United Kingdom, and Oxford Tropical Network Overseas Programs in southeast Asia and Africa, will develop a new approach for the large-scale surveillance of bacterial antibiotic resistance in low-income settings.

Honorine Ward of Tufts Medical Center in the U.S. will develop a three-dimensional model of the human intestine for rapid screening of drugs targeting the parasite Cryptosporidium, which causes potentially lethal diarrhea in young children in developing countries. Developing drugs against Cryptosporidium has been particularly difficult, partly because of the limited understanding of the parasites behavior in the human intestine, and particularly of the effect of malnutrition, which commonly co-occurs with infection and likely contributes to disease severity.

Samuel Arnold of the University of Washington in the U.S. will develop methods to evaluate drug candidates for treating Cryptosporidium infections, which cause severe diarrhea particularly in young children from developing countries. There are no effective drugs against the Cryptosporidium parasite. This is partly because when it infects humans it becomes isolated in specific cells lining the gastrointestinal tract, which is where a drug would also need to be located at sufficient concentrations to be effective.

Xun Suo of China Agricultural University in China will develop a rabbit model of cryptosporidiosis that mimics the human disease, which presents as severe diarrhea particularly in young children, to help identify new treatments. Current animal models of infection by the parasite Cryptosporidium are suboptimal: mice are not naturally infected, while pigs and calves can be infected but are expensive and more difficult to manage, and none show the same symptoms as humans. Rabbits are naturally infected by Cryptosporidium and display human-related symptoms.

Anastasios Tsaousis of the University of Kent in the United Kingdom will build a screening platform to identify drugs that can be used to treat diarrhea caused by the parasite Cryptosporidium, which is the second major cause of death in children under five years old in developing countries. There are currently no effective drugs for treating Cryptosporidium, largely because it cannot easily be grown in the laboratory making it difficult to study and test for new drugs.

William Witola of the University of Illinois in the U.S. will help develop new drugs for treating children infected with the protozoa Cryptosporidium by using a gene knockdown approach to evaluate candidate drug targets. Found in contaminated water, Cryptosporidium is the second most common cause of potentially lethal diarrhea in young children in developing countries. There are no safe and effective drugs available due largely to the lack of genetic tools for studying Cryptosporidium in the laboratory.

Christopher Huston of the University of Vermont in the U.S. will screen for compounds that inhibit differentiation of Cryptosporidium in culture in vitro. Lack of a continuous in vitro culture system impedes drug development for Cryptosporidium, which causes substantial morbidity and mortality in developing countries. Cryptosporidium infects intestinal cell lines but it quickly differentiates from replicating asexual to non-replicating sexual forms.

Paul Kelly of Queen Mary and Westfield College in the United Kingdom and the University of Zambia will work with colleagues to identify and evaluate candidate biomarkers of environmental enteropathy, which causes growth failure in children in the developing world. Possible markers of enteropathy in serum and gut secretions will be correlated with two severe clinical outcomes, impaired nutrient absorption, and loss of gut barrier function leading to bacteria entering the bloodstream. The aim is to drive the development of new treatments.

Asad Ali of Aga Khan University in Pakistan and co-­investigators will test a selected group of candidate biomarkers to identify and monitor environmental enteropathy, which causes malnutrition and stunting. The biomarkers, which include markers of inflammation and enteric pathogens, will be tested in blood, urine and stools, and correlated with structural features of the small bowel using biopsies from malnourished children. They will also attempt to identify new candidate biomarkers in these biopsies using mRNA sequencing.