A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis
The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using <i>Heligmosomoides polygyrus bakeri</i> (<i>Hpb</i>), 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<sub>2</sub> (PGE<sub>2</sub>) as a major immune regulatory mechanism of heGDH. The induction of PGE<sub>2</sub> 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.
Authors
- Ulrich Fabien Prodjinotho (ORCID: https://orcid.org/0000-0002-3851-706X)
- Antonie Lechner (ORCID: https://orcid.org/0000-0002-1636-3354)
- Franziska Hartung (ORCID: https://orcid.org/0000-0002-3063-0949)
- Francesca Alessandrini (ORCID: https://orcid.org/0000-0002-9854-8968)
- Stefanie M. Hauck (ORCID: https://orcid.org/0000-0002-1630-6827)
- Sina Bohnacker (ORCID: https://orcid.org/0000-0002-8804-7238)
- André Mourão (ORCID: https://orcid.org/0000-0003-0764-9868)
- Stefan Bohn (ORCID: https://orcid.org/0000-0001-9196-622X)
- Dominique Thomas (ORCID: https://orcid.org/0000-0002-4153-3669)
- Michael Sattler (ORCID: https://orcid.org/0000-0002-1594-0527)
- Tarvi Teder (ORCID: https://orcid.org/0000-0002-8489-3955)
- Julia Esser‐von Bieren (ORCID: https://orcid.org/0000-0003-1898-9382)
- David Voehringer (ORCID: https://orcid.org/0000-0001-6650-0639)
- Arie Geerlof (ORCID: https://orcid.org/0000-0001-7295-9948)
- Alessandro Quaranta (ORCID: https://orcid.org/0000-0002-3167-3772)
- Eya Ben Salah (ORCID: https://orcid.org/0000-0002-0619-880X)
- Agnieszka M. Kabat (ORCID: https://orcid.org/0000-0003-1916-5983)
- Matthias Johannes Feige (ORCID: https://orcid.org/0000-0001-5435-4312)
- Jesper Z. Haeggström (ORCID: https://orcid.org/0000-0002-1823-5153)
- Fiona Henkel
- Minhaz Ud‐Dean (ORCID: https://orcid.org/0000-0002-7428-3432)
- Craig E. Wheelock (ORCID: https://orcid.org/0000-0002-8113-0653)
- Robert Gurke (ORCID: https://orcid.org/0000-0001-8218-1295)
- Edward J. Pearce (ORCID: https://orcid.org/0000-0003-1001-9656)
- A. König (ORCID: https://orcid.org/0000-0001-8265-2499)
- Benedikt Spitzlberger (ORCID: https://orcid.org/0009-0005-5791-5118)
- Clarissa Prazeres da Costa
- Christiane Boeckel
- P.‐J. Jakobsson
- Sandra Riemer
Institutions
- Goethe University Frankfurt (DE)
- Karolinska University Hospital (SE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Center for Environmental Health (US)
- Karolinska Institutet (SE)
- Helmholtz Zentrum München (DE)
- Universitätsklinikum Erlangen (DE)
- Protein Express (United States) (US)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- German Center for Infection Research (DE)
- Institute of Medical Microbiology and Hygiene (DE)
- Max Planck Institute of Biochemistry (DE)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- Technical University of Munich (DE)
- University of Lausanne (CH)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-12-06
- DOI
- https://doi.org/10.1126/sciimmunol.adl1467
- Citations
- 10
- Primary Topic
- Parasites and Host Interactions
- Type
- article
- Field-Weighted Citation Impact
- 5.16