HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33

  • Immunity. 2017 Oct 17;47(4):739-751.e5. doi: 10.1016/j.immuni.2017.09.015.
Megan Osbourn  1 ,  Dinesh C Soares  1 ,  Francesco Vacca  1 ,  E Suzanne Cohen  2 ,  Ian C Scott  2 ,  William F Gregory  1 ,  Danielle J Smyth  3 ,  Matilda Toivakka  4 ,  Andrea M Kemter  3 ,  Thierry le Bihan  5 ,  Martin Wear  6 ,  Dennis Hoving  7 ,  Kara J Filbey  8 ,  James P Hewitson  9 ,  Holly Henderson  1 ,  Andrea Gonzàlez-Cìscar  4 ,  Claire Errington  1 ,  Sonja Vermeren  1 ,  Anne L Astier  1 ,  William A Wallace  10 ,  Jürgen Schwarze  1 ,  Alasdair C Ivens  8 ,  Rick M Maizels  11 ,  Henry J McSorley  12
Affiliations
  • 1. MRC Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
  • 2. Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Cambridge CB21 6GH, UK.
  • 3. Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK; Wellcome Centre for Molecular Parasitology, Institute for Infection, Immunity and Inflammation, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, UK.
  • 4. MRC Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK.
  • 5. SynthSys, The Kings Buildings, University of Edinburgh, Edinburgh EH9 3BF, UK.
  • 6. The Edinburgh Protein Production Facility (EPPF), Wellcome Trust Centre for Cell Biology (WTCCB), University of Edinburgh, King's Buildings, Max Born Crescent, Mayfield Road, Edinburgh EH9 3BF, UK.
  • 7. Wellcome Centre for Molecular Parasitology, Institute for Infection, Immunity and Inflammation, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, UK.
  • 8. Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK.
  • 9. Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK; Centre for Immunology and Infection, Department of Biology, University of York YO10 5DD, York, UK.
  • 10. Department of Pathology, Laboratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.
  • 11. Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK; Wellcome Centre for Molecular Parasitology, Institute for Infection, Immunity and Inflammation, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, UK. Electronic address: [email protected].
  • 12. MRC Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK. Electronic address: [email protected].
PMID: 29045903 DOI: 10.1016/j.immuni.2017.09.015
Abstract

Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse Parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing Parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine's activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both Infection and allergy.

Keywords
IL-33; allergy; asthma; helminth; immunomodulation; parasite.