Heparan Sulphate Binding Increases the Half-Life and Activity of the Suppressive HpARI Proteins, HpARI1 and HpARI2

Concepts de base

The parasitic nematode Heligmosomoides polygyrus bakeri secretes a family of proteins (HpARI) that modulate the host immune response by binding to the cytokine IL-33, with HpARI1 and HpARI2 suppressing and HpARI3 enhancing IL-33 activity; the differential activity is determined by the ability of HpARI1 and HpARI2, but not HpARI3, to bind to heparan sulphate, which increases their half-life and retains them at the site of infection.

Résumé

Colomb, F., Ogunkanbi, A., Jamwal, A., Dong, B., Maizels, R. M., Finney, C. A. M., Wasmuth, J. D., Higgins, M. K., & McSorley, H. J. (2024). IL-33-binding HpARI family homologues with divergent effects in suppressing or enhancing type 2 immune responses. Infection and Immunity, 92(3), e0039523. https://doi.org/10.1128/iai.00395-23

This study investigates the molecular mechanisms underlying the divergent effects of the HpARI protein family, secreted by the parasitic nematode Heligmosomoides polygyrus bakeri (Hpb), on the host immune response to the cytokine IL-33.

Idées clés tirées de

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

by Colomb,F., J... à www.biorxiv.org 05-11-2024

https://www.biorxiv.org/content/10.1101/2024.05.06.592731v2

Questions plus approfondies

How might the differential binding of HpARI proteins to heparan sulphate affect the development of host adaptive immunity to H. polygyrus bakeri?

Answer: The differential binding of HpARI proteins to heparan sulphate (HS) likely plays a crucial role in shaping the host's adaptive immune response to H. polygyrus bakeri in a multifaceted manner:

Localization and Retention: HpARI1 and HpARI2, by binding to HS in the extracellular matrix (ECM), are likely retained at the site of infection in the intestinal mucosa. This localized retention allows for concentrated and sustained suppression of local IL-33 signaling. As IL-33 is a potent activator of Type 2 immunity, which is essential for expelling H. polygyrus bakeri, this localized suppression could dampen the activation and recruitment of effector cells like eosinophils and Th2 cells, hindering parasite clearance.

Modulation of IL-33 Gradient: HpARI3, lacking HS binding, can diffuse more freely. This could create a gradient of IL-33 activity, with suppression dominant at the site of infection due to HpARI1/2, and potential amplification in distal tissues due to HpARI3. This could have implications for the development of systemic versus localized immunity.

Impact on Antigen Presentation: The localized suppression of IL-33 by HpARI1/2 could indirectly affect antigen presentation. IL-33 can promote the maturation and activation of dendritic cells, key antigen-presenting cells that initiate adaptive immunity. By suppressing IL-33, HpARI1/2 might limit the ability of dendritic cells to effectively prime T cells against H. polygyrus bakeri antigens, thus delaying or reducing the adaptive response.

Skewing T Cell Responses: While the paper focuses on innate responses, the altered IL-33 milieu created by differential HpARI binding could indirectly influence T cell differentiation. A strong Th2 response is needed for parasite expulsion. If HpARI3-mediated IL-33 amplification in distal sites favors Treg induction (as the paper speculates), this could further dampen the effectiveness of the adaptive response against the parasite.
In essence, the HpARI family's intricate interplay with HS and IL-33 allows H. polygyrus bakeri to fine-tune the host's immune response, creating a localized immunosuppressive environment while potentially limiting the development of a robust systemic adaptive response that would threaten its survival.

Could the HpARI proteins be binding to other components of the extracellular matrix, and if so, how might this affect their function?

Answer: It is highly plausible that HpARI proteins, particularly HpARI1 and HpARI2, could bind to other ECM components besides heparan sulphate. This is because their positively charged CCP1 domain could interact with negatively charged molecules abundant in the ECM. Here are some potential binding partners and their functional implications:

Hyaluronic Acid: This abundant ECM component is negatively charged. Binding to hyaluronic acid could further anchor HpARI1/2, creating a denser localized concentration and enhancing their IL-33 blocking activity.

Fibronectin: This glycoprotein plays a crucial role in cell adhesion and migration. HpARI binding to fibronectin could interfere with immune cell recruitment to the site of infection, further suppressing the immune response.

Proteoglycans: Beyond HS, other proteoglycans with negatively charged glycosaminoglycan chains (e.g., chondroitin sulfate, dermatan sulfate) could interact with HpARI1/2. This could further diversify their localization and retention within the ECM.

Collagen: While less likely due to its overall neutral charge, specific collagen subtypes or regions with exposed negative charges could potentially interact with HpARIs. This could influence ECM organization and impact immune cell access.
The functional consequences of binding to these additional ECM components could be diverse:

Prolonged Half-Life: Similar to HS, binding to other ECM components could shield HpARI1/2 from degradation, extending their half-life and enhancing their suppressive effects.

Altered Bioavailability: Binding to different ECM components could create reservoirs of HpARIs with varying release kinetics, influencing their spatial and temporal availability to modulate IL-33.

Modulation of Immune Cell Trafficking: By binding to ECM components involved in cell adhesion and migration, HpARIs could directly interfere with the movement of immune cells, preventing them from reaching the site of infection.

Disruption of Tissue Repair: The ECM plays a crucial role in tissue repair and remodeling. HpARI binding to ECM components could interfere with these processes, potentially contributing to chronic inflammation and tissue damage.
Further research is needed to identify specific interactions between HpARIs and other ECM components and to fully elucidate their functional implications in the context of H. polygyrus bakeri infection.

What are the evolutionary implications of parasites evolving mechanisms to fine-tune the host immune response, rather than simply evading it?

Answer: The evolution of sophisticated mechanisms to fine-tune, rather than simply evade, the host immune response, as exemplified by H. polygyrus bakeri and its HpARI proteins, carries significant evolutionary implications:

Enhanced Parasite Survival: By delicately modulating the host immune response, parasites can establish a long-term infection without causing excessive damage that would jeopardize their survival or that of the host. This balanced approach ensures a continuous source of resources and transmission opportunities for the parasite.

Reduced Host Pathology: Simply evading the immune response could lead to uncontrolled parasite growth and severe host pathology. Fine-tuning allows for a more stable host-parasite relationship, minimizing damage and increasing the chances of host survival, which ultimately benefits the parasite.

Selection for Immune Evasion: The host immune system exerts selective pressure on parasites. Those capable of fine-tuning the immune response gain a survival advantage, leading to the selection and transmission of these advantageous traits to subsequent generations.

Co-Evolutionary Arms Race: The evolution of immune modulation by parasites fuels an ongoing co-evolutionary arms race with the host immune system. As parasites develop new strategies to fine-tune immunity, the host immune system evolves countermeasures, leading to a dynamic interplay between host and parasite.

Implications for Parasite Control: Understanding the intricate mechanisms of immune modulation employed by parasites is crucial for developing effective control strategies. Simply targeting parasite antigens might not be sufficient if the parasite can effectively manipulate the immune response.

Insights into Immune System Regulation: Studying how parasites fine-tune the immune response can provide valuable insights into the complex regulatory mechanisms governing the mammalian immune system. This knowledge can be leveraged to develop novel therapeutic interventions for immune-mediated diseases.
In conclusion, the evolution of immune fine-tuning mechanisms by parasites reflects a successful strategy for long-term survival within the host. This intricate co-evolutionary dance between parasite and host has shaped the immune system and continues to offer valuable insights into its complexities.