PROJECT SUMMARY Cryptosporidiosis, a disease caused by the protozoan parasite Cryptosporidium, poses a significant global health threat, particularly affecting young children in developing regions and immunocompromised individuals. Despite its severity, there are currently no vaccines or effective therapies available, highlighting the urgent need for innovative solutions. This research proposal addresses this critical gap by focusing on two key objectives: establishing reliable small mouse models of cryptosporidiosis and unraveling the intricacies of IFN-γ responses during C. parvum infection. Our preliminary data underscore the significance of the TLR11/TLR12 complex in detecting Cryptosporidium and regulating IFN-γ-mediated immune responses. Additionally, we have developed mouse models with cell-specific deficiencies in IFN-γ production and responsiveness, providing valuable tools to enhance our understanding of host defense against Cryptosporidium. The primary objective of this project is to elucidate the fundamental pathways governing the host's ability to combat C. parvum infections at mucosal sites. To achieve this, our research is structured around specific aims that explore the roles of TLR and IFN-γ pathways in mucosal immunity. This knowledge will provide insights into the molecular and cellular responses that ultimately determine the outcome of C. parvum infections at mucosal sites. Our research endeavors aim to contribute to the development of innovative strategies to combat this devastating disease.