Heligmosomoides polygyrus produces homologues of HpARI and HpBARI which have increased activity against human immune targets

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Authors

A Ogunkanbi1; A Jamal2; Z Sekne2; M Higgins2; S Cohen3; H J McSorley1
1 The division of Cell Signalling and Immunology, University of Dundee, Dundee, United Kingdom, UK;  2 Department of Biochemistry, University of Oxford, Oxford, United Kingdom, UK;  3 Bioscience Asthma, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom, UK

Discussion

Infection with parasitic helminths is known to be associated with the reduction of allergic asthma. This has been linked to the ability of parasites to release molecules with immunomodulatory ability, thus promoting their own survival. H. polygyrus is a gastrointestestinal parasitic helminth which causes chronic infections in mice, and has multiple known immunomodulatory activities. IL-33 is a key cytokine involved in the activation of type-2 anti-parasite and allergic responses. H. polygyrus releases HpARI and HpBARI: proteins capable of suppressing IL-33-induced allergic asthma. Here, we show that these proteins show suppressive effects against allergic asthma irrespective of their route of administration, either locally or systemically. Furthermore, data from H. polygyrus infections suggests that HpBARI can act in the peritoneal cavity and lung after release from this purely enteric parasite. These data suggest modulation of immune responses by these parasite proteins can be systemic as well as local. Homologues of both HpARI and HpBARI exist in the H. polygyrus genome, which have increased activity against human IL-33 responses. Surface Plasmon Resonance (SPR) experiments were used to assess affinity of the homologues for their immune targets, showing that these homologues have 10-100-fold higher affinity for the human targets, compared to the prototypic HpARI and HpBARI proteins. Furthermore, when tested in a humanised mouse model, or on in vitro human PBMCs, these homologues showed much increased activity in blocking human IL-33 responses. Our findings offer the possibility to develop new parasite-derived therapeutics against human allergic diseases which could be administered systemically.

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