The role of the tuft cell inflammasome in infection

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Project summary The intestinal epithelium is exposed to different classes of pathogens and is not only instrumental as a first line of defense against invasion of the host, but also signals to immune cells in the underlying lamina propria when pathogens are detected. The NAIP/NLRC4 inflammasome has emerged as an important innate immune sensor in intestinal epithelial cells (IECs) in bacterial gastrointestinal infection, leading to rapid extrusion of infected cells and release of cytokines and eicosanoids upon pathogen recognition. The role of innate immune sensing and the NAIP/NLRC4 inflammasome at the level of individual subtypes of IEC is not well understood. Recently, we discovered that tuft cells uniquely among IECs release the eicosanoid prostaglandin D2 (PGD2) after inflammasome activation. Tuft cells are a rare subtype of IECs primarily known for their role in anti- parasitic immunity. The role of tuft cells during bacterial infection in general as well as the role of released PGD2 in intestinal immunity is unclear. Our preliminary data show that tuft cell inflammasome activation leads to increased tissue levels of IL-22, an antibacterial cytokine that can be produced by TH17 cells or innate lymphoid cells (ILCs), and that tuft cell inflammasome expression protects from small intestinal bacterial colonization. Based on our preliminary data and published data on PGD2 receptor expression we propose a tuft cell- ILC3 communication axis via PGD2. We hypothesize that tuft cells are central sentinels of infection status of the small intestine and capable of shifting the polarization of the intestinal immune response. We aim to define the pathway leading to IL-22 increase after tuft cell inflammasome activation using in vivo models of tuft cell specific inflammasome activation and conditional epithelial PGD2 synthase and ILC3 PGD2 receptor deficiency. Further we will define the importance of tuft cell infection and inflammasome activation during bacterial gastroenteritis, using a model of infection clearance with an attenuated strain of Salmonella that does not lead to systemic infection. We will also explore the capacity of the tuft cell inflammasome to affect an ongoing type 2 immune response during co-infection with a parasite, Nippostrongylus brasiliensis, and Salmonella. These studies will greatly contribute to our understanding of epithelial cell type specific pathogen sensing and the intestinal immune systems capacity to react to different types of infection. This proposal brings together studies in the Rauch laboratory at Oregon Health and Science University and the expertise of the Tait Wojno laboratory at the University of Washington. Unique expertise in the Tait Wojno laboratory in the use of murine models of helminth infection will be leveraged to collaborate on exciting studies that complement expertise in the Rauch laboratory in epithelial cell biology, inflammasome biology, and intestinal bacterial infection.