This project will investigate how we can use proteins derived from a parasitic worm to either amplify or suppress "IL-33", a protein used for communication within the immune system. IL-33 is released on damage to various barrier sites (lung, skin, gut), and can lead to either allergic or inflammatory responses, depending on the context. These responses can be beneficial, e.g. they can efficiently clear bacterial infections, or they can be detrimental, e.g. they can lead to the development of allergic or inflammatory damage such as in asthma or acute respiratory distress syndrome. Therefore being able to effectively "tune" the IL-33 pathway up or down would be a powerful technique for treating a wide range of diseases including asthma, eczema, fungal or bacterial infections, and acute respiratory distress syndrome. We have identified two proteins derived from a single parasitic worm (Heligmosomoides polygyrus) which act to suppress IL-33 responses; we have named these proteins HpARI and HpBARI. Suppression of IL-33 responses is advantageous to parasites, as it allows them to avoid triggering immune responses which could lead to their ejection or damage to their host. When we produced a mutant form of one of these IL-33-suppressive proteins, we found the mutant form had the surprising effect of amplifying (rather than suppressing) IL-33 responses due to stabilisation of the IL-33 molecule. Therefore we can use these proteins and mutants to either increase or decrease IL-33 responses and potentially treat a long list of diseases in which IL-33 has a causative, or curative, role. This project will investigate the use of these proteins and their derivatives in mouse systems where IL-33 drives allergic responses (such as in asthma), damaging inflammatory responses (such as in acute lung injury or acute respiratory distress syndrome) or beneficial anti-bacterial responses (such as in pneumonia). We will translate findings from the mouse towards human responses by using genetically-engineered mice which express the human form of the IL-33 molecule, and stimulating human blood cells with human IL-33 in the lab, and testing whether our proteins affect the responses of these cells. Furthermore, we will engineer hybrid molecules, taking the active regions of our proteins, and combining them with proteins normally present in our blood. This will have the advantage that the resulting proteins will be largely ignored by the immune system as they look like one of the body's own proteins. This avoids a common problem (known as "immunogenicity") of using foreign proteins as medicines, where the immune system rejects the protein, preventing it from carrying out its function. These engineered proteins will be further assessed for activity against IL-33 responses and for immunogenicity (the level of recognition by the immune system) in mouse and human tests, as described above. In summary, this project will investigate and characterise new parasite-derived proteins which can suppress or amplify the immune response, with the potential to be used as new medicines or tools for research in a range of allergic, inflammatory and infectious diseases.