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

Sci Immunol. 2024 Dec 6;9(102):eadl1467. doi: 10.1126/sciimmunol.adl1467. Epub 2024 Dec 6.

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.

MeSH terms

  • Animals
  • Epigenesis, Genetic* / immunology
  • Female
  • Helminth Proteins / genetics
  • Helminth Proteins / immunology
  • Immune Evasion / immunology
  • Immunity, Cellular
  • Macrophages* / immunology
  • Macrophages* / parasitology
  • Mice
  • Mice, Inbred C57BL*
  • Nematospiroides dubius / immunology
  • Prostaglandins / immunology
  • Strongylida Infections / immunology
  • Strongylida Infections / parasitology

Substances

  • Prostaglandins
  • Helminth Proteins