Abstract
The IL-33-ST2 pathway is an important initiator of type 2 immune responses. We previously characterised the HpARI protein secreted by the model intestinal nematode Heligmosomoides polygyrus, which binds and blocks IL-33. Here, we identify H. polygyrus Binds Alarmin Receptor and Inhibits (HpBARI) and HpBARI_Hom2, both of which consist of complement control protein (CCP) domains, similarly to the immunomodulatory HpARI and Hp-TGM proteins. HpBARI binds murine ST2, inhibiting cell surface detection of ST2, preventing IL-33-ST2 interactions, and inhibiting IL-33 responses in vitro and in an in vivo mouse model of asthma. In H. polygyrus infection, ST2 detection is abrogated in the peritoneal cavity and lung, consistent with systemic effects of HpBARI. HpBARI_Hom2 also binds human ST2 with high affinity, and effectively blocks human PBMC responses to IL-33. Thus, we show that H. polygyrus blocks the IL-33 pathway via both HpARI which blocks the cytokine, and also HpBARI which blocks the receptor.
Highlights
Intestinal nematodes such as human hookworms are highly successful parasites, infecting almost 500 million people worldwide (Loukas et al, 2016)
From studies of the murine model intestinal nematode Heligmosomoides polygyrus, we recently identified the H. polygyrus Alarmin Release Inhibitor (HpARI), a protein secreted by a murine intestinal nematode which binds to DNA and IL-33 in necrotic host cells, tethering the cytokine in the nucleus, preventing its release while simultaneously directly blocking binding to its receptor ST2 (Osbourn et al, 2017)
Alternaria allergen administration induced increased expression of ST2, and while HpARI reduced levels of ST2 to that of the PBS control we found that HES suppressed detection of ST2 on ILC2s to levels far below baseline (Figure 1A–B)
Summary
Intestinal nematodes such as human hookworms are highly successful parasites, infecting almost 500 million people worldwide (Loukas et al, 2016) They are associated with immunosuppression (Bethony et al, 2006), which in turn may reduce the prevalence of immune-mediated diseases such as asthma. From studies of the murine model intestinal nematode Heligmosomoides polygyrus, we recently identified the H. polygyrus Alarmin Release Inhibitor (HpARI), a protein secreted by a murine intestinal nematode which binds to DNA and IL-33 in necrotic host cells, tethering the cytokine in the nucleus, preventing its release while simultaneously directly blocking binding to its receptor ST2 (Osbourn et al, 2017). We identify the H. polygyrus Binds Alarmin Receptor and Inhibits (HpBARI), a protein secreted by the parasite which consists of two atypical CCP domains. This study highlights the importance of IL-33 modulation to H. polygyrus, expands the family of CCP domain containing protein immunomodulators from the parasite, and identifies a novel agent with potential for treatment of human IL-33mediated disease
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
