A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis
Bohnacker S, Henkel FD, Hartung F, Geerlof A, Riemer S, Prodjinotho UF, Salah EB, Dias Mourão AS, Bohn S, Teder T, Thomas D, Gurke R, Boeckel C, Ud-Dean M, König AC, Quaranta A, Alessandrini F, Lechner A, Spitzlberger B, Kabat AM, Pearce E, Haeggström JZ, Hauck SM, Wheelock CE, Jakobsson PJ, Sattler M, Vöhringer D, Feige MJ, da Costa CP, Esser-Von Bieren J (2024)
Publication Type: Journal article
Publication year: 2024
Journal
Book Volume: 9
Article Number: eadl1467
Journal Issue: 102
DOI: 10.1126/sciimmunol.adl1467
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.
Authors with CRIS profile
Involved external institutions
Université de Lausanne (UNIL)
Switzerland (CH)
Karolinska Institute
Sweden (SE)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Technische Universität München (TUM)
Germany (DE)
Max-Planck-Institut für Biochemie / Max Planck Institute of Biochemistry
Germany (DE)
Goethe-Universität Frankfurt am Main
Germany (DE)
Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics
Germany (DE)
Karolinska University Hospital / Karolinska Universitetssjukhuset
Sweden (SE)
Switzerland (CH)
Karolinska Institute
Sweden (SE)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Technische Universität München (TUM)
Germany (DE)
Max-Planck-Institut für Biochemie / Max Planck Institute of Biochemistry
Germany (DE)
Goethe-Universität Frankfurt am Main
Germany (DE)
Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics
Germany (DE)
Karolinska University Hospital / Karolinska Universitetssjukhuset
Sweden (SE)
How to cite
APA:
Bohnacker, S., Henkel, F.D., Hartung, F., Geerlof, A., Riemer, S., Prodjinotho, U.F.,... Esser-Von Bieren, J. (2024). A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis. Science immunology, 9(102). https://doi.org/10.1126/sciimmunol.adl1467
MLA:
Bohnacker, Sina, et al. "A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis." Science immunology 9.102 (2024).
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