HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33

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...

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Published in:	Immunity (Cambridge, Mass.) Mass.), 2017-10, Vol.47 (4), p.739-751.e5
Main Authors:	Osbourn, Megan, Soares, Dinesh C., Vacca, Francesco, Cohen, E. Suzanne, Scott, Ian C., Gregory, William F., Smyth, Danielle J., Toivakka, Matilda, Kemter, Andrea M., le Bihan, Thierry, Wear, Martin, Hoving, Dennis, Filbey, Kara J., Hewitson, James P., Henderson, Holly, Gonzàlez-Cìscar, Andrea, Errington, Claire, Vermeren, Sonja, Astier, Anne L., Wallace, William A., Schwarze, Jürgen, Ivens, Alasdair C., Maizels, Rick M., McSorley, Henry J.
Format:	Article
Language:	eng
Subjects:	Allergens - immunology Allergies allergy Alternaria - immunology Amino Acid Sequence Animals Apoptosis Asthma Blotting, Western Candidates Cytokines Deoxyribonucleic acid Disease DNA Eosinophils - immunology Food allergies Fractionation Gangrene helminth Helminth Proteins - genetics Helminth Proteins - immunology Helminth Proteins - metabolism Host-Parasite Interactions - immunology Humans IL-33 Immune response Immunity Immunity, Innate - immunology Immunology immunomodulation Infections Interleukin-1 Receptor-Like 1 Protein Interleukin-33 - genetics Interleukin-33 - immunology Interleukin-33 - metabolism Interleukins Leukocytes (eosinophilic) Life Sciences Lymphocytes - immunology Macular degeneration Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Nematospiroides dubius - genetics Nematospiroides dubius - immunology Nematospiroides dubius - metabolism parasite Parasites Predictive control Protein Binding - immunology Proteins Receptors, Interleukin - immunology Receptors, Interleukin - metabolism Sequence Homology, Amino Acid Strongylida Infections - immunology Strongylida Infections - metabolism Strongylida Infections - parasitology Studies Tethering Viral infections
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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. [Display omitted] •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 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.
ISSN:	1074-7613 1097-4180