A netrin domain-containing protein secreted by the human hookworm Necator americanus protects against CD4 T cell transfer colitis
A netrin domain-containing protein secreted by the human hookworm Necator americanus protects against CD4 T cell transfer colitis
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DOI：
10.1016/j.trsl.2021.02.012
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发表时间：
2021-05-04
影响因子：
7.8
通讯作者：
Loukas，Alex
中科院分区：
文献类型：
--
作者：
Buitrago，Geraldine;Pickering，Darren;Loukas，Alex
人类与其胃肠道寄生虫之间共享的共生关系为发现炎性疾病的新疗法提供了机会。这种现象的一个主要例子是人类和蛔虫的相互作用，如钩虫，美洲钩虫。流行病学观察、动物研究和使用实验性人类钩虫感染的临床试验表明，钩虫可以以安全和耐受性良好的方式抑制炎症，其免疫调节特性的关键在于其分泌的蛋白质组。在此，我们描述了从N. Americanussecretome，并探讨其在治疗溃疡性结肠炎小鼠模型肠道炎症中的潜力。其中一种蛋白质，后来命名为Na-AIP-1，在TNBS诱导的急性结肠炎模型中，当给药时，可有效抑制疾病。这种保护作用在慢性结肠炎的更稳健的CD 4 T细胞转移模型中得到了验证，在该模型中，EscheracticNa-AIP-1减少了肠道中的T细胞依赖性1型细胞因子应答和相关的肠道病理学。机制研究表明，CD 11 c+细胞的耗竭废除了Na-AIP-1的保护性抗钙化作用。结肠炎T细胞转移模型中结肠组织的下一代测序显示，Na-AIP-1诱导了与1型炎症相关的代谢和信号通路（特别是TNF）下调相关的转录组学特征。最后，Na-AIP-1与人单核细胞衍生的M1巨噬细胞系的共培养导致TNF的分泌显著降低。Na-AIP-1现在是临床开发作为治疗人类炎症性肠病的新型治疗剂的候选者。
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 of humans and roundworms such as the hookworm,Necator americanus. Epidemiological observations, animal studies and clinical trials using experimental human hookworm infection show that hookworms can suppress inflammation in a safe and well-tolerated way, and that the key to their immunomodulatory properties lies within their secreted proteome. Herein we describe the identification of 2 netrin domain-containing proteins from theN. americanussecretome, and explore their potential in treating intestinal inflammation in mouse models of ulcerative colitis. One of these proteins, subsequently namedNa-AIP-1, was effective at suppressing disease when administered prophylactically in the acute TNBS-induced model of colitis. This protective effect was validated in the more robust CD4 T cell transfer model of chronic colitis, where prophylacticNa-AIP-1 reduced T-cell-dependent type-1 cytokine responses in the intestine and the associated intestinal pathology. Mechanistic studies revealed that depletion of CD11c+ cells abrogated the protective anticolitic effect ofNa-AIP-1. Next generation sequencing of colon tissue in the T-cell transfer model of colitis revealed thatNa-AIP-1 induced a transcriptomic profile associated with the downregulation of metabolic and signaling pathways involved in type-1 inflammation, notably TNF. Finally, co-culture ofNa-AIP-1 with a human monocyte-derived M1 macrophage cell line resulted in significantly reduced secretion of TNF.Na-AIP-1 is now a candidate for clinical development as a novel therapeutic for the treatment of human inflammatory bowel diseases.