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
Department of Immunobiology, Université de Lausanne, Epalinges, Switzerland.
Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Munich, German Research Center for Environmental Health, Munich, Germany.
Sci Immunol. 2024 Dec 6;9(102):eadl1467. doi: 10.1126/sciimmunol.adl1467.
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.
蠕虫寄生虫逃避宿主免疫的分子机制尚未完全明确。在使用()的肠道蠕虫感染小鼠模型中,我们发现蠕虫谷氨酸脱氢酶(heGDH)通过抑制巨噬细胞介导的宿主防御来推动寄生虫的慢性感染。结合RNA测序、染色质免疫沉淀测序和靶向脂质组学,我们确定前列腺素E(PGE)是heGDH的主要免疫调节机制。heGDH对PGE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)的诱导需要p300介导的组蛋白乙酰化,而该酶的催化活性通过2-羟基戊二酸抑制巨噬细胞合成促进2型的白三烯。相比之下,免疫调节因子的诱导涉及heGDH的N末端,可能是通过介导与蛋白质组学鉴定的细胞靶点(CD64和GPNMB)的相互作用。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,通过表观遗传方式靶向2型巨噬细胞活化并建立慢性感染。