Biology subjects

Ogunkanbi, A.

Publications and source records attributed to Ogunkanbi, A..

4 recordsLinked to original sources

bioRxiv2026

Evolutionary adaptation of helminth immunomodulators to their hosts

Background: Parasitic nematodes have evolved secreted effector proteins which interact with host molecules to modulate the host immune response. These interactions can be highly specific and are under strong selective pressure. Here, we investigate the host-pathogen interaction between Heligmosomoides bakeri and its natural host Mus musculus, and between H. polygyrus and its natural host Apodemus sylvaticus. We focus on the Alarmin Release Inhibitor family (previously called HpARI) produced by heligmosomid parasites, which interact with IL-33 and heparan sulphate. Results: Using comparative genomics, we identified duplications and diversifications of the ARI family including multiple copies of ARI1 and conserved ARI3 homologues in both H. bakeri and H. polygyrus. We identify a new family member, HpolARI4, encoded by H. polygyrus, as well as a more distant homologue, HmixARI, encoded by Heligmosomum mixtum, a parasite of the bank vole (Myodes glareolus). Our functional assays identify that HpolARI4 preferentially blocks A. sylvaticus IL-33 but has little activity against M. musculus IL-33, whereas HbakARI2 is highly specific for M. musculus IL-33. We furthermore show differential interaction with host heparan sulphate, with HbakARI2 and HpolARI4 showing high affinity binding, whereas HbakARI3 shows no binding. We further test this family against non-host human IL-33 and show that functional suppression can be achieved by HbakARI3 in vitro and in vivo. Conclusion: By integrating genomic data, structural insights, and functional assays, we reveal how the expansion and diversification of the ARI family drive host-specific IL-33 modulation, providing a molecular model for nematode-host co-evolution.

immunology↗

bioRxiv2024

Heparan sulphate binding controls in vivo half-life of the HpARI protein family

The parasitic nematode Heligmosomoides polygyrus bakeri secretes the HpARI family, which bind to IL-33, either suppressing (HpARI1 and HpARI2) or enhancing (HpARI3) responses to the cytokine. We previously showed that HpARI2 also bound to DNA via its first Complement Control Protein (CCP1) domain. Here, we find that HpARI1 can also bind DNA, while HpARI3 cannot. Through the production of HpARI2/HpARI3 CCP1 domain-swapped chimeras, DNA-binding ability can be transferred, and correlates with in vivo half-life of administered proteins. We found that HpARI1 and HpARI2 (but not HpARI3) also binds to the extracellular matrix component heparan sulphate (HS), and structural modelling showed a basic charged patch in the CCP1 domain of HpARI1 and HpARI2 (but not HpARI3) which could facilitate these interactions. Finally, a mutant of HpARI2 was produced which lacked DNA and HS binding, and was also shown to have a short half-life in vivo. Therefore, we propose that during infection the suppressive HpARI1 and HpARI2 proteins have long-lasting effects at the site of deposition due to DNA and/or extracellular matrix interactions, while HpARI3 has a shorter half-life due to a lack of these interactions.

immunology↗

bioRxiv2023

IL-33-binding HpARI family homologues with divergent effects in suppressing or enhancing Type 2 immune responses

HpARI is an immunomodulatory protein secreted by the intestinal nematode Heligmosomoides polygyrus bakeri, which binds and blocks IL-33. Here, we find that the H. polygyrus bakeri genome contains 3 HpARI family members, and that these have different effects on IL-33-dependent responses in vitro and in vivo, with HpARI1+2 suppressing, and HpARI3 amplifying these responses. All HpARIs have sub-nanomolar affinity for mouse IL-33, however HpARI3 does not block IL-33-ST2 interactions. Instead, HpARI3 stabilises IL-33, increasing the half-life of the cytokine and amplifying responses to it in vivo. Together these data show that H. polygyrus bakeri secretes a family of HpARI proteins with both overlapping and distinct functions, comprising a complex immunomodulatory arsenal of host-targeted proteins.

immunology↗

bioRxiv2020

A truncated form of HpARI stabilises IL-33, amplifying responses to the cytokine.

1The 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. Mechanistically, we found that HpARI_CCP1/2 is able to bind to and stabilise 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 stabilisation in vivo, and describes a new tool for IL-33 research.

immunology↗