Our lab works on therapeutic development for the treatment of gastrointestinal infections. Recently, this work has focused on treatments for shigellosis which results from oral ingestion of the Gram-negative bacteria Shigella. It is estimated that there are close to 90 million shigellosis cases annually, and it is the second leading cause of diarrheal death for all age groups with 212,000 deaths per year. Despite a global need to reduce this substantial disease burden, no human vaccine candidates have been approved. Given the well-established role of the innate immune system in vaccine response, we are focused on improving our understanding of how the gastrointestinal innate immune system reacts to Shigella infection. Thorough investigation of gastrointestinal innate immune responses to Shigella infection has been hindered by inadequate in vitro models and a dearth of robust animal disease models. Recently, our lab has generated improved mouse models of Shigella infection, but there is substantial room for additional in vitro model development. The development of biorelevant Shigella in vitro models has concentrated on the incorporation of human intestinal epithelial cells (hIECs). While studies with hIECs have drastically improved our understanding of Shigella adhesion and invasion, these initial models lack components known to stimulate Shigella virulence (e.g., mucus, bile salts) and cell types that play an essential role in Shigella pathogenesis (e.g., macrophages). We are incorporating these missing elements into an in vitro model derived from human intestinal epithelial stem cells which will provide an in vivo ‘like” environment to better characterize the innate immune response to Shigella infection. We believe our improved in vitro and in vivo models will accelerate the development of vaccines and small molecule treatments for shigellosis.