Structural basis for IL-33 recognition and its antagonism by the helminth effector protein HpARI

Interleukin 33 (IL-33) plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri (Hp) secretes the Alarmin Release Inhibitor (HpARI), a potent effector protein which suppresses protective immune responses and asthma in its host by inhibiting IL-33 signalling. Here we reveal the structure of HpARI bound to mouse IL-33. HpARI contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison shows that this overlaps with the binding site on IL-33 for its receptor, ST2, preventing formation of a signalling complex. Truncations of HpARI which lack the large loop from CCP3 are not able to block IL-33-mediated signalling in a cell-based assay and in an in vivo model of asthma. This shows that direct competition between HpARI and ST2 is responsible for suppression of IL-33-dependent responses. This first structure of IL-33 bound to a pathogen-based inhibitor will guide future approaches to design therapeutics blocking IL-33-mediated allergic and inflammatory conditions.