Hookworm Secreted Extracellular Vesicles Interact With Host Cells and Prevent Inducible Colitis in Mice.
Hookworm Secreted Extracellular Vesicles Interact With Host Cells and Prevent Inducible Colitis in Mice.
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DOI：
10.3389/fimmu.2018.00850
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发表时间：
2018
影响因子：
7.3
通讯作者：
Loukas A
中科院分区：
文献类型：
--
作者：
Eichenberger RM;Ryan S;Jones L;Buitrago G;Polster R;Montes de Oca M;Zuvelek J;Giacomin PR;Dent LA;Engwerda CR;Field MA;Sotillo J;Loukas A
胃肠道（GI）寄生虫，特别是钩虫，已经进化到对宿主造成最小的伤害，使它们能够建立慢性感染。这是通过创造免疫调节环境来介导的。事实上，钩虫是如此有效的炎症抑制剂，它们已被用于临床试验，以治疗炎症性肠病（IBD）和乳糜泻。由于最近描述的蠕虫（蠕虫）分泌细胞外囊泡（EV），外泌体样EV从不同的蠕虫已被表征，其在寄生虫-宿主相互作用中的突出作用已被强调。在这里，我们分析了来自啮齿动物寄生虫巴西日本圆线虫的EV，该寄生虫已被用作人类钩虫感染的模型。N.巴西EV（Nb-EV）被小鼠肠道类器官积极内化，表明在驱动寄生中的作用。我们使用蛋白质组学和RNA-Seq来分析Nb-EV的分子组成。我们鉴定了81种蛋白质，包括经常存在于外泌体中的蛋白质（如四跨膜蛋白、烯醇化酶、14-3-3蛋白和热休克蛋白）和27种精子包被蛋白样细胞外蛋白。RNA-Seq分析揭示了52种miRNA种类，其中许多与参与炎症调节的小鼠基因相关。为了确定GI线虫EV是否具有免疫调节特性，我们评估了它们在诱导型化学性结肠炎小鼠模型中抑制GI炎症的潜力。从N。巴西鞭虫的囊泡，而不是来自鞭虫鼠鞭虫的囊泡或来自葡萄的对照囊泡，保护接受单次腹膜内注射EV的小鼠的肠道免受结肠炎炎症。在EV处理小鼠的结肠组织中，与结肠炎病理学相关的关键细胞因子（IL-6、IL-1β、IFNγ和IL-17 a）受到显著抑制。相比之下，在Nb-EV处理的小鼠中检测到高水平的抗炎细胞因子IL-10。蠕虫EV中含有的蛋白质和miRNA在开发治疗蠕虫感染以及由免疫系统失调引起的慢性非感染性疾病（例如IBD）的药物中具有巨大的潜在应用。
Gastrointestinal (GI) parasites, hookworms in particular, have evolved to cause minimal harm to their hosts, allowing them to establish chronic infections. This is mediated by creating an immunoregulatory environment. Indeed, hookworms are such potent suppressors of inflammation that they have been used in clinical trials to treat inflammatory bowel diseases (IBD) and celiac disease. Since the recent description of helminths (worms) secreting extracellular vesicles (EVs), exosome-like EVs from different helminths have been characterized and their salient roles in parasite–host interactions have been highlighted. Here, we analyze EVs from the rodent parasite Nippostrongylus brasiliensis, which has been used as a model for human hookworm infection. N. brasiliensis EVs (Nb-EVs) are actively internalized by mouse gut organoids, indicating a role in driving parasitism. We used proteomics and RNA-Seq to profile the molecular composition of Nb-EVs. We identified 81 proteins, including proteins frequently present in exosomes (like tetraspanin, enolase, 14-3-3 protein, and heat shock proteins), and 27 sperm-coating protein-like extracellular proteins. RNA-Seq analysis revealed 52 miRNA species, many of which putatively map to mouse genes involved in regulation of inflammation. To determine whether GI nematode EVs had immunomodulatory properties, we assessed their potential to suppress GI inflammation in a mouse model of inducible chemical colitis. EVs from N. brasiliensis but not those from the whipworm Trichuris muris or control vesicles from grapes protected against colitic inflammation in the gut of mice that received a single intraperitoneal injection of EVs. Key cytokines associated with colitic pathology (IL-6, IL-1β, IFNγ, and IL-17a) were significantly suppressed in colon tissues from EV-treated mice. By contrast, high levels of the anti-inflammatory cytokine IL-10 were detected in Nb-EV-treated mice. Proteins and miRNAs contained within helminth EVs hold great potential application in development of drugs to treat helminth infections as well as chronic non-infectious diseases resulting from a dysregulated immune system, such as IBD.