Biology subjects

Colomb, F.

Publications and source records attributed to Colomb, F..

4 recordsLinked to original sources

bioRxiv2024

Vaccination against helminth IL-33-modulators permits immune-mediated parasite ejection

The murine intestinal nematode Heligmosomoides polygyrus bakeri powerfully modulates the host immune response. This is achieved in part through the HpARI family (HpARI1/2/3), which act on IL-33, and the HpBARI family (HpBARI and HpBARI_Hom2), which act on ST2. Here, we find that this immunomodulation is evident only in the first week of infection, with abrogation of ST2 detection and systemic suppression of IL-33-dependent responses. Vaccination with individual HpARI or HpBARI family members raised antibody responses which could block these proteins immunomodulatory activities. During infection, vaccination could release the host from immunosuppression: HpARI2 vaccination resulted in much increased ILC2 and Th2 immunity, with heightened serum IL-4 and IL-5 responses, but did not abrogate ST2 suppression. In contrast, a HpBARI+HpBARI_Hom2 vaccination cocktail resulted in abrogation of ST2 suppression, and again increased Th2 immunity and serum cytokine responses. Either of the HpARI2 or the HpBARI cocktail vaccinations provided significant protection against subsequent H. polygyrus bakeri infection. We therefore show a proof of principle that vaccination with immunomodulatory proteins can protect the host against infection, and can be used as a tool for blocking the effects of specific parasite-derived proteins.

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↗

bioRxiv2023

Structural basis for IL-33 recognition and its antagonism by the helminth effector protein HpARI

Interleukin 33 (IL-33) plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri (Hp) secretes the Alarmin Release Inhibitor (HpARI), a potent effector protein which suppresses protective immune responses and asthma in its host by inhibiting IL-33 signalling. Here we reveal the structure of HpARI bound to mouse IL-33. HpARI contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison shows that this overlaps with the binding site on IL-33 for its receptor, ST2, preventing formation of a signalling complex. Truncations of HpARI which lack the large loop from CCP3 are not able to block IL-33-mediated signalling in a cell-based assay and in an in vivo model of asthma. This shows that direct competition between HpARI and ST2 is responsible for suppression of IL-33-dependent responses. This first structure of IL-33 bound to a pathogen-based inhibitor will guide future approaches to design therapeutics blocking IL-33-mediated allergic and inflammatory conditions.

microbiology↗