TY - JOUR
T1 - A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis
AU - Bohnacker, Sina
AU - Henkel, Fiona D.R.
AU - Hartung, Franziska
AU - Geerlof, Arie
AU - Riemer, Sandra
AU - Prodjinotho, Ulrich F.
AU - Salah, Eya Ben
AU - Dias Mourão, André Santos
AU - Bohn, Stefan
AU - Teder, Tarvi
AU - Thomas, Dominique
AU - Gurke, Robert
AU - Boeckel, Christiane
AU - Ud-Dean, Minhaz
AU - König, Ann Christine
AU - Quaranta, Alessandro
AU - Alessandrini, Francesca
AU - Lechner, Antonie
AU - Spitzlberger, Benedikt
AU - Kabat, Agnieszka M.
AU - Pearce, Edward
AU - Haeggström, Jesper Z.
AU - Hauck, Stefanie M.
AU - Wheelock, Craig E.
AU - Jakobsson, Per Johan
AU - Sattler, Michael
AU - Voehringer, David
AU - Feige, Matthias J.
AU - da Costa, Clarissa Prazeres
AU - Esser-Von Bieren, Julia
N1 - Publisher Copyright:
copyright © 2024 the authors
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85211750904&partnerID=8YFLogxK
U2 - 10.1126/sciimmunol.adl1467
DO - 10.1126/sciimmunol.adl1467
M3 - Article
AN - SCOPUS:85211750904
SN - 2470-9468
VL - 9
JO - Science Immunology
JF - Science Immunology
IS - 102
M1 - eadl1467
ER -