HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33

Megan Osbourn,Matilda Toivakka,Dennis Hoving,Thierry Le Bihan,James P Hewitson,Claire Errington,Jürgen Schwarze,Danielle J Smyth,Andrea M Kemter,Rick M Maizels,Sonja Vermeren,Henry J Mcsorley,Kara J Filbey,Holly Henderson,Francesco Vacca,Andrea Gonzàlez-Cìscar,Dinesh C Soares,William F Gregory,Alasdair Ivens ,Ian Scott ,William Wallace ,Suzanne Cohen ,Anne Astier ,Martin A Wear

doi:10.1016/j.immuni.2017.09.015

Abstract

SummaryInfection 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.

Highlights

Infection with helminth parasites negatively correlates with prevalence of allergic disease, and parasitic infection is associated with immunosuppression (Maizels and McSorley, 2016)
In Vitro Suppression of IL-33 by Heligmosomoides polygyrus (HES) Previous studies established that HES ablates detectable IL-33 in the bronchoalveolar milieu after Alternaria allergen administration, suppressing downstream allergic responses (McSorley et al, 2014)
To further investigate the IL-33-suppressive activity of HES, we developed an in vitro assay for IL-33 release: a single cell suspension of naıve total murine lung cells cultured for 1 hr in the presence of Alternaria allergen and HES

Summary

Graphical 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. Highlights d HpARI is a suppressor of IL-33 release and consequent allergic sensitization d HpARI binds active IL-33 and nuclear DNA, tethering IL-33 within necrotic cells d HpARI is active against both human and murine IL-33. 2017, Immunity 47, 739–751 October 17, 2017 a 2017 The Author(s).

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