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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)
DOI PMC
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Ccp4 Suite; Cells; Inflammation; Polarization; Activation; Expression; Phenotype; Proteome; Type-1; Focus
ISSN (print) / ISBN 2470-9468
e-ISSN 2470-9468
Zeitschrift Science immunology
Quellenangaben Band: 9, Heft: 102, Seiten: , Artikelnummer: eadl1467 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington, DC
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Allergy Research (IAF)
Institute of Structural Biology (STB)
Institute of Computational Biology (ICB)
CF Metabolomics & Proteomics (CF-MPC)
Förderungen 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