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 E 2 (PGE 2 ) as a major immune regulatory mechanism of heGDH. The induction of PGE 2 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.

中文翻译：

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蠕虫酶通过表观遗传靶向前列腺素合成来破坏巨噬细胞介导的免疫


蠕虫寄生虫逃避宿主免疫的分子机制尚不完全清楚。在使用 Heligmosomoides polygyrus bakeri （ Hpb ） 的肠道蠕虫感染小鼠模型中，我们表明蠕虫谷氨酸脱氢酶 （heGDH） 通过抑制巨噬细胞介导的宿主防御来驱动寄生虫慢性病。结合 RNA-seq、ChIP-seq 和靶向脂质组学，我们确定前列腺素 E 2 （PGE 2） 是 heGDH 的主要免疫调节机制。heGDH 诱导 PGE 2 和其他免疫调节因子，包括 IL-12 家族细胞因子和吲哚胺 2,3-双加氧酶 1，需要 p300 介导的组蛋白乙酰化，而该酶的催化活性抑制巨噬细胞通过 2-羟基戊二酸合成 2 型促进白三烯。相比之下，免疫调节因子的诱导通过潜在介导与蛋白质组学鉴定的细胞靶标 （CD64 和 GPNMB） 的相互作用而涉及 heGDH N 末端。2 型细胞因子抵消了 heGDH 对宿主防御的抑制作用，表明 2 型免疫可以限制蠕虫驱动的免疫逃避。因此，蠕虫利用一种普遍存在的代谢酶在表观遗传学上靶向 2 型巨噬细胞激活并建立慢性。