Authors

H McSorley¹;  ¹ University of Dundee, UK

Discussion

Intestinal nematodes are associated with modulation of host immune responses, suppression the development of allergic disease and allowing their persistence in the host. Studying the mechanisms of parasite immunomodulation could lead to both new treatments for allergic diseases, and new targets for vaccination. The intestinal parasitic nematode Heligmosomoides polygyrus bakeri secretes an array of immunomodulatory proteins. The HpARI family (HpARI1, HpARI2 and HpARI3) act on the IL-33 cytokine, while the HpBARI family (HpBARI and HpBARI_Hom2) act on the IL-33 receptor, ST2. These 5 proteins have disparate effects on IL-33 responses in models of allergic asthma: while most of these proteins suppress IL-33 responses, HpARI3 alone has the surprising effect of amplifying responses in IL-33-dependent models. Our current work uses vaccination, antibody blockade, protein binding and structural studies to elucidate the effects of these immunomodulatory proteins. We find that H. polygyrus co-opts the IL-33 pathway to block its pro-type 2 immune response effects in situ, while amplifying the cytokine’s distal regulatory T cell-inducing effects. We further find that administration of specific members of these immunomodulatory families as vaccines can provide effective immunity to the parasite. Our work provides a basis for further studies on immunomodulatory proteins from parasitic helminths, their unexpectedly complex mechanisms of action, and their potential for use in vaccines and therapeutic regimens.