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      HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          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.

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          Highlights

          • HpARI is a suppressor of IL-33 release and consequent allergic sensitization
          • HpARI binds active IL-33 and nuclear DNA, tethering IL-33 within necrotic cells
          • HpARI is active against both human and murine IL-33

          Abstract

          Osbourn et al identified HpARI, a protein secreted by a helminth parasite that is capable of suppressing allergic responses. HpARI binds to IL-33 (a critical inducer of allergy) and nuclear DNA, preventing the release of IL-33 from necrotic epithelial cells.

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          Most cited references 61

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              We describe a comparative protein modelling method designed to find the most probable structure for a sequence given its alignment with related structures. The three-dimensional (3D) model is obtained by optimally satisfying spatial restraints derived from the alignment and expressed as probability density functions (pdfs) for the features restrained. For example, the probabilities for main-chain conformations of a modelled residue may be restrained by its residue type, main-chain conformation of an equivalent residue in a related protein, and the local similarity between the two sequences. Several such pdfs are obtained from the correlations between structural features in 17 families of homologous proteins which have been aligned on the basis of their 3D structures. The pdfs restrain C alpha-C alpha distances, main-chain N-O distances, main-chain and side-chain dihedral angles. A smoothing procedure is used in the derivation of these relationships to minimize the problem of a sparse database. The 3D model of a protein is obtained by optimization of the molecular pdf such that the model violates the input restraints as little as possible. The molecular pdf is derived as a combination of pdfs restraining individual spatial features of the whole molecule. The optimization procedure is a variable target function method that applies the conjugate gradients algorithm to positions of all non-hydrogen atoms. The method is automated and is illustrated by the modelling of trypsin from two other serine proteinases.
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                Author and article information

                Contributors
                Journal
                Immunity
                Immunity
                Immunity
                Cell Press
                1074-7613
                1097-4180
                17 October 2017
                17 October 2017
                : 47
                : 4
                : 739-751.e5
                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
                [4 ]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
                [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 ]Centre for Immunology and Infection, Department of Biology, University of York YO10 5DD, York, UK
                [8 ]Department of Pathology, Laboratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
                Author notes
                []Corresponding author rick.maizels@ 123456glasgow.ac.uk
                [∗∗ ]Corresponding author henry.mcsorley@ 123456ed.ac.uk
                [9]

                These authors contributed equally

                [10]

                Senior author

                [11]

                Lead contact

                Article
                S1074-7613(17)30426-0
                10.1016/j.immuni.2017.09.015
                5655542
                29045903
                © 2017 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                Categories
                Article

                Immunology

                parasite, allergy, asthma, immunomodulation, helminth, il-33

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