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Bohnacker, S. ; Henkel, F. ; Hartung, F. ; Geerlof, A. ; Riemer, S. ; Prodjinotho, U.F.* ; Salah, E.B.* ; Mourao, A. ; Bohn, S. ; Teder, T.* ; Thomas, D.* ; Gurke, R.* ; Böckel, C. ; Ud-Dean, M. ; König, A.-C. ; Quaranta, A.* ; Alessandrini, F. ; Lechner, A. ; Spitzlberger, B. ; Kabat, A.M.* ; Pearce, E.J.* ; Haeggström, J.Z.* ; Hauck, S.M. ; Wheelock, C.E.* ; Jakobsson, P.J.* ; Sattler, M. ; Voehringer, D.* ; Feige, M.J.* ; da Costa, C.P.* ; Esser-von Bieren, J.

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

Sci. Immunol. 9:eadl1467 (2024)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Ccp4 Suite; Cells; Inflammation; Polarization; Activation; Expression; Phenotype; Proteome; Type-1; Focus

ISSN (print) / ISBN 2470-9468

e-ISSN 2470-9468

Journal Science immunology

Quellenangaben Volume: 9, Issue: 102, Article Number: eadl1467

Publisher American Association for the Advancement of Science (AAAS)

Publishing Place Washington, DC

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute for Allergy Research (IAF)
Institute of Structural Biology (STB)
Institute of Computational Biology (ICB)
CF Metabolomics & Proteomics (CF-MPC)

Grants Swedish Research Council
Swiss National Science Foundation
Helmholtz Young Investigator grant by the Helmholtz Initiative and Networking Fund
German Federal Ministry of Education and Research (BMBF)
German Research Foundation