The apicomplexan parasite Cryptosporidium is a leading cause of death due to diarrheal disease in young children, particularly in the context of malnutrition, milder infections often result in growth faltering. The incidence of cryptosporidiosis drops off sharply after the age of two in areas of high transmission, yet in regions with low transmission adults remain susceptible, as demonstrated by frequent outbreaks in the U.S. More than 50% of waterborne disease in the U.S. is caused by this parasite which is resistant to water chlorination and considered a category B potential bioterrorism agent. The epidemiology in children suggests that initial infection results in long lived protective immunity, a phenomenon also observed in the context of veterinary cryptosporidiosis. Harnessing this immunity into a vaccine could prevent the disease and dramatically impact child mortality and development. However, there are significant gaps in our knowledge of the mechanisms that underlie immunity to Cryptosporidium. We developed a new natural model of Cryptosporidium infection in immunocompetent C57BL/6 mice that mirrors important aspects of human cryptosporidiosis and in which host and parasite are genetically tractable. This proposal assembles an interdisciplinary team of experienced parasite molecular biologist and immunologist to define how the infected enterocyte senses infection, how it responds to and restricts infection, and how it interacts with dendritic cells and T cells to trigger and execute a protective immune response. This research will impact our fundamental understanding of immunity in the gut and drive translation towards prevention of an important contributor of child mortality. !