A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis
Sina Bohnacker, Fiona Henkel, Franziska Hartung, Arie Geerlof, Sandra Riemer, Ulrich Fabien Prodjinotho, Eya Ben Salah, André Mourão, Stefan Bohn, Tarvi Teder, Dominique Thomas, Robert Gurke, Christiane Boeckel, Minhaz Ud‐Dean, A. König, Alessandro Quaranta, Francesca Alessandrini, Antonie Lechner, Benedikt Spitzlberger, Agnieszka M. Kabat, Edward J. Pearce, Jesper Z. Haeggström, Stefanie M. Hauck, Craig E. Wheelock, P.‐J. Jakobsson, Michael Sattler, David Voehringer, Matthias J. Feige, Clarissa Prazeres da Costa, Julia Esser‐von Bieren
Abstract
The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using Heligmosomoides polygyrus bakeri ( Hpb ), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E 2 (PGE 2 ) as a major immune regulatory mechanism of heGDH. The induction of PGE 2 and other immunoregulatory factors, including IL-12 family cytokines and indoleamine 2,3-dioxygenase 1, by heGDH required p300-mediated histone acetylation, whereas the enzyme’s catalytic activity suppressed the synthesis of type 2–promoting leukotrienes by macrophages via 2-hydroxyglutarate. By contrast, the induction of immunoregulatory factors involved the heGDH N terminus by potentially mediating interactions with cellular targets (CD64 and GPNMB) identified by proteomics. Type 2 cytokines counteracted suppressive effects of heGDH on host defense, indicating that type 2 immunity can limit helminth-driven immune evasion. Thus, helminths harness a ubiquitous metabolic enzyme to epigenetically target type 2 macrophage activation and establish chronicity.