
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.


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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.

### Competing Interest Statement

The authors have declared no competing interest.

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

heparan-sulphate-binding-increases-the-half-life-and-activity-of-the-suppressive-hpari-proteins-hpari1-and-hpari2


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