ジャーナル: Sci Immunol / 年: 2024 タイトル: A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis. 著者: Sina Bohnacker / Fiona D R Henkel / Franziska Hartung / Arie Geerlof / Sandra Riemer / Ulrich F Prodjinotho / Eya Ben Salah / André Santos Dias Mourão / Stefan Bohn / Tarvi Teder / ...著者: Sina Bohnacker / Fiona D R Henkel / Franziska Hartung / Arie Geerlof / Sandra Riemer / Ulrich F Prodjinotho / Eya Ben Salah / André Santos Dias Mourão / Stefan Bohn / Tarvi Teder / Dominique Thomas / Robert Gurke / Christiane Boeckel / Minhaz Ud-Dean / Ann-Christine König / Alessandro Quaranta / Francesca Alessandrini / Antonie Lechner / Benedikt Spitzlberger / Agnieszka M Kabat / Edward Pearce / Jesper Z Haeggström / Stefanie M Hauck / Craig E Wheelock / Per-Johan Jakobsson / Michael Sattler / David Voehringer / Matthias J Feige / Clarissa Prazeres da Costa / Julia Esser-von Bieren / 要旨: The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using (), we show that helminthic glutamate ...The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using (), 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 (PGE) as a major immune regulatory mechanism of heGDH. The induction of PGE 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.