A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis

Sina Bohnacker, Fiona D.R. Henkel, Franziska Hartung, Arie Geerlof, Sandra Riemer, Ulrich F. Prodjinotho, Eya Ben Salah, André Santos Dias Mourão, Stefan Bohn, Tarvi Teder, Dominique Thomas, Robert Gurke, Christiane Boeckel, Minhaz Ud-Dean, Ann Christine König, Alessandro Quaranta, Francesca Alessandrini, Antonie Lechner, Benedikt Spitzlberger, Agnieszka M. KabatEdward Pearce, Jesper Z. Haeggström, Stefanie M. Hauck, Craig E. Wheelock, Per Johan Jakobsson, Michael Sattler, David Voehringer, Matthias J. Feige, Clarissa Prazeres da Costa, Julia Esser-Von Bieren

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

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 E2 (PGE2) as a major immune regulatory mechanism of heGDH. The induction of PGE2 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.

OriginalspracheEnglisch
Aufsatznummereadl1467
FachzeitschriftScience Immunology
Jahrgang9
Ausgabenummer102
DOIs
PublikationsstatusVeröffentlicht - Dez. 2024

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