Chromatin Landscape of Macrophages Following Helminth Enzyme Exposure Targeting Prostaglandin Synthesis
The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of chronic intestinal helminth infection, we identify helminthic glutamate dehydrogenase (heGDH) as an essential factor for parasite chronicity by using antibody mediated neutralization or treatment with exogenous recombinant heGDH. Macrophages efficiently internalize heGDH and represent a major target of the enzyme in vivo. Combining RNA-seq, ChIP-seq, targeted lipidomics and inhibitor studies, we identify prostaglandin E2 (PGE2) as a major immune regulatory mechanism of heGDH. The induction of PGE2 and further immune regulatory factors (IL-12 family cytokines, IDO1) by heGDH depended on the p300-mediated acetylation of histones. While the enzyme's catalytic activity was dispensable for key immune regulatory functions, an N-terminal handle-like structure distinct from mammalian GDHs may confer interaction of heGDH with its targets (CD64, GPNMB), identified via proteomics. Thus, helminths employ a ubiquitous metabolic enzyme to epigenetically target macrophages and establish chronicity. Overall design: Chromatin immunoprecipitation DNA-Seq sequencing (ChIP-seq) for histone modification H3K4