Suppression and amplification of IL-33 responses by an intestinal nematode

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Abstract:

Heligmosomoides polygyrus is an intestinal nematode with multiple immunomodulatory activities mediated by its secreted products. We previously identified HpARI, a secreted protein which blocks IL-33, inhibiting type 2 immune responses. HpARI mechanism of action is via dual binding to genomic DNA and directly to IL-33. This allows HpARI to tether IL-33 to genomic DNA within necrotic epithelial cells, and makes it an effective inhibitor of IL-33.

We have since found that H. polygyrus secretes 3 HpARI homologues: HpARI1, HpARI2 and HpARI3. While HpARI2 suppresses IL-33 responses in in vitro type 2 innate lymphoid cell assays and in in vivo models of allergic asthma, HpARI3 does the opposite, amplifying IL-33-dependent responses in vitro and in vivo. HpARI3 lacks the DNA-binding activity of HpARI2, and has altered binding characteristics for IL-33 – this results in stabilisation of this labile cytokine, extending its half-life and amplifying responses to it. We are currently investigating the hypothesis that context and timing-dependent activities of HpARI2 and HpARI3 allow H. polygyrus to suppress the anti-parasite activity of IL-33 in acute responses, while co-opting the immunoregulatory and pro-resolution activities of IL-33 in chronic responses.

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