Molecular regulators of the alarmin IL-33 in health and disease

IL-33 is a critical cytokine in allergy, obesity, helminth infection, sepsis, and respiratory viral infection. Blockade of IL-33 (or its receptor, ST2) is currently being trialled in a range of allergic and inflammatory conditions, including Covid-19. The cytokine has a short half-life on release, but conversely has effects at distal sites and over long periods. Furthermore, innate immune cells in the intestine are poorly responsive to IL-33, but susceptibility to intestinal helminths is strongly controlled by IL-33. This project will investigate: 1) How, at a protein structural level, parasite proteins effectively block IL-33 responses. Determination of the effects on the parasite and host of blocking parasite modulation of the IL-33 pathway. 2) What are the roles and targets of IL-33 released from the intestinal epithelium, both locally (in parasite infection) and systemically (in diet-induced obesity). 3) The role of soluble IL-33 receptor in stabilisation of IL-33, and its effects at distal sites. To achieve these aims will we will use structural biology, in vivo models of IL-33-dependent responses, creation of cell-specific ST2-deficient mouse strains, and generation of a soluble ST2-deficient mouse. Finally we will use human blood samples and three-dimensional culture methods to ensure translation of these findings to humans.