A netrin domain-containing protein secreted by the human hookworm Necator americanus protects against CD4 T cell transfer colitis

The symbiotic relationships shared between humans and their gastrointestinal parasites present opportunities to discover novel therapies for inflammatory diseases. A prime example of this phenomenon is the interaction roundworms such as hookworm, Necator americanus. Epidemiological observations, animal studies clinical trials using experimental human hookworm infection show that hookworms can suppress inflammation in a safe well-tolerated way, key immunomodulatory properties lies within secreted proteome. Herein we describe identification 2 netrin domain-containing proteins from N. americanus secretome, explore potential treating intestinal mouse models ulcerative colitis. One these proteins, subsequently named Na-AIP-1, was effective at suppressing disease when administered prophylactically acute TNBS-induced model This protective effect validated more robust CD4 T cell transfer chronic colitis, where prophylactic Na-AIP-1 reduced T-cell-dependent type-1 cytokine responses intestine associated pathology. Mechanistic revealed depletion CD11c+ cells abrogated anticolitic Na-AIP-1. Next generation sequencing colon tissue T-cell colitis induced transcriptomic profile with downregulation metabolic signaling pathways involved inflammation, notably TNF. Finally, co-culture monocyte-derived M1 macrophage line resulted significantly secretion now candidate development therapeutic treatment bowel AT GLANCE COMMENTARYBuitrago, G et al. BackgroundInflammatory diseases (IBD) are debilitating conditions caused by uncontrolled intestine. Existing treatments often poorly tolerated minimally effective. In search new anti-inflammatory modalities, took inspiration co-evolution parasitic worms (helminths). Translational SignificanceHerein secrete protein limits IBD symptoms gut delivered multiple IBD. administration suppresses several line, could be further developed efficacious maintenance therapy Buitrago, Inflammatory blanket term describing Crohn's (CD), (UC) handful less common, but similarly debilitating, tract. IBDs chronic, refractory disorders classified accordance nature respective immunological pathological features; ultimately, characterized compromised epithelial barrier integrity hyper-responsive conditions. 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