Author response: A helminth-derived suppressor of ST2 blocks allergic responses

Vacca, Francesco; Chauché, Caroline; Jamwal, Abhishek; Heieis, Graham A.; Webster, Holly; Ogunkanbi, Adefunke; Sekne, Zala; Gregory, William F.; Wear, Martin A.; Perona-Wright, Georgia; Higgins, M.K.; Nys, Josquin; Cohen, E. Suzanne; McSorley, Henry J.

doi:10.7554/elife.54017.sa2

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“…In order to negate this response, and allow persistence of the parasite in the host, H. polygyrus secretes multiple immunomodulatory factors, including Hp-TGM, a protein mimic of host TGF-β (5), and microRNA-containing extracellular vesicles (6) which modulate transcription of multiple host genes, including suppression of Suppression of Tumorigenicity 2 (ST2), the IL-33 receptor. Furthermore, our recent work shows that H. polygyrus secretes HpBARI, a protein which binds and blocks ST2 (7). We previously showed that the parasite also secretes the H. polygyrus Alarmin Release Inhibitor (HpARI), which blocks IL-33 responses (8).…”

Section: Introductionmentioning

confidence: 99%

A Truncated Form of HpARI Stabilizes IL-33, Amplifying Responses to the Cytokine

et al. 2020

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The murine intestinal nematode Heligmosomoides polygyrus releases the H. polygyrus Alarmin Release Inhibitor (HpARI)-a protein which binds to IL-33 and to DNA, effectively tethering the cytokine in the nucleus of necrotic cells. Previous work showed that a non-natural truncation consisting of the first 2 domains of HpARI (HpARI_CCP1/2) retains binding to both DNA and IL-33, and inhibited IL-33 release in vivo. Here, we show that the affinity of HpARI_CCP1/2 for IL-33 is significantly lower than that of the full-length protein, and that HpARI_CCP1/2 lacks the ability to prevent interaction of IL-33 with its receptor. When HpARI_CCP1/2 was applied in vivo it potently amplified IL-33-dependent immune responses to Alternaria alternata allergen, Nippostrongylus brasiliensis infection and recombinant IL-33 injection, in direct contrast to the IL-33-suppressive effects of full-length HpARI. Mechanistically, we found that HpARI_CCP1/2 is able to bind to and stabilize IL-33, preventing its degradation and maintaining the cytokine in its active form. This study highlights the importance of IL-33 inactivation, the potential for IL-33 stabilization in vivo, and describes a new tool for IL-33 research.

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