Enteric infectious diseases continue to represent a major cause of morbidity and mortality worldwide. In addition to gastrointestinal pathogens that have been known for centuries, there continues to be an emergence of enteric disease agents as a product of manmade and natural changes in the environment. The appearance of antibiotic resistance and the lateral transfer of virulence factors have also impacted our ability to deal with well known pathogens. To counter these infectious disease threats, novel methods of studying these pathogens are needed. We have assembled an interdisciplinary team to address the need for novel alternative model systems for enteric diseases research. With expertise in viral and bacterial pathogenesis, immunology, tissue engineering, stem cell biology, infectious diseases and bioengineering, this team will utilize human intestinal or- ganoids (HIOs) generated from human pluripotent stem cells (hPSCs) as a model gut epithelium. Three integrated projects will address the common specific aim of utilizing HIOs as a system to investigate the interaction between the intestinal epithelium, immune cells, microbiota and enteric pathogens. The first project will focus on the interaction of the HIO epithelium with normal members of the gut microbiota and specific enteric pathogens. Changes in the function of both the microbes and the HIO epithelium will be investigated. The second project will focus on interactions between the model epithelium found in the organoids and cellular elements of the immune system. Human immune cells will be allowed to interact with HIOs in both the presence and absence of microbes. The final project will employ a bioengineering approach to create a system that both facilitates the use of HIOs as a platform for scientific discovery and serves as a flexible platform for drug discovery and testing. These three projects will form an integrated cooperative research center that will involve investigators with a wide range of complementary expertise. Successful completion of the three projects will generate a powerful new system to study the biology of enteric disease agents and a platform for the development of novel therapeutics for their control.
Infections of the gastrointestinal tract with microbes remains a significant health problem. To develop a new method to study these important infections, we will use a recently developed method that involves the creation of organoids from human stem cells. Organoids are hollow balls of cells that resemble the lining of the intestines. We have shown that we can infect organoids with microbes. We will study how microbes affect the human intestinal organoid epithelium and how the microbes themselves change after contact with the human epithelium. We will also look at how the cells of the immune system interact with the organoid, with and without the presence of microbes. Finally, we will use bioengineering to develop microfluidic systems that will allow us to create a scalable model that can be used to study enteric pathogenesis, or that can be used in the development and testing of new treatments for enteric infections.
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