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

Bohnacker, Sina; Henkel, Fiona D R; Hartung, Franziska; Geerlof, Arie; Riemer, Sandra; Prodjinotho, Ulrich F; Salah, Eya Ben; Mourão, André Santos Dias; Bohn, Stefan; Teder, Tarvi; Thomas, Dominique; Gurke, Robert; Boeckel, Christiane; Ud-Dean, Minhaz; König, Ann-Christine; Quaranta, Alessandro; Alessandrini, Francesca; Lechner, Antonie; Spitzlberger, Benedikt; Kabat, Agnieszka M; Pearce, Edward; Haeggström, Jesper Z; Hauck, Stefanie M; Wheelock, Craig E; Jakobsson, Per-Johan; Sattler, Michael; Voehringer, David; Feige, Matthias J; da Costa, Clarissa Prazeres; Esser-von Bieren, Julia     «

Bohnacker, Sina; Henkel, Fiona D R; Hartung, Franziska; Geerlof, Arie; Riemer, Sandra; Prodjinotho, Ulrich F; Salah, Eya Ben; Mourão, André Santos Dias; Bohn, Stefan; Teder, Tarvi; Thomas, Dominique; Gurke, Robert; Boeckel, Christiane; Ud-Dean, Minhaz; König, Ann-Christine; Quaranta, Alessandro; Alessandrini, Francesca; Lechner, Antonie; Spitzlberger, Benedikt; Kabat, Agnieszka M; Pearce, Edward; Haeggström, Jesper Z; Hauck, Stefanie M; Wheelock, Craig E; Jakobsson, Per-Johan; Sattler, Michael;...     »

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.      «

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 imm...     »