PROJECT SUMMARY Pathogen recognition receptors and their associated adaptors are essential for the prompt detection of pathogens and the subsequent initiation of effective host responses and restoration of homeostasis. Over the last decade, Nod-like receptors (NLRs) have been on the forefront of innate immune research, and several groundbreaking studies have been published, to which my research has contributed. Leishmania spp. are parasites with global health importance, yet the role of NLRs and their adaptors during Leishmania spp. infection has been an understudied area. Receptor interacting protein kinase 2 (RIPK2) is an essential adaptor downstream of cytoplasmic sensors NLRC1 and NLRC2, and play an important role in a wide variety of clinical settings including bacterial, viral and fungal infections, as well as non-infectious inflammatory diseases such as multiple sclerosis, inflammatory bowel disease and metabolic diseases. However, the role of RIPK2 during cutaneous leishmaniasis remain unknown. In this grant, we propose to investigate the precise cellular and molecular mechanisms involving RIPK2 during Leishmania major (L. major)-induced cutaneous disease. Our preliminary work has already elucidated several exciting features of the role of RIPK2 during L. major infection. We found that RIPK2- deficient mice are highly susceptible to L. major infection. Unexpectedly, mice deficient in NLRC2 or both NLRC1/NLRC2 are dispensable in L. major infection suggesting a novel sensor that function upstream of RIPK2. Moreover, RIPK2 interacted with CARD9 to provide protection against L. major. Based on these preliminary data, we propose that a novel Dectin-1/RIPK2/CARD9 signaling axis modulates anti-leishmanial immunity. Successful completion of this project will yield a better understanding of RIPK2 biology in general, unveil a novel pathway involving RIPK2 in signal transduction, and potentially identify therapeutic targets to ameliorate Leishmania spp.-associated pathology. 1