Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
Lydia Becker Institute of Immunology and Inflammation, Wellcome Trust Centre for Cell Matrix Research and Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
PLoS Pathog. 2019 Jan 14;15(1):e1007265. doi: 10.1371/journal.ppat.1007265. eCollection 2019 Jan.
The whipworm Trichuris trichiura is a soil-transmitted helminth that dwells in the epithelium of the caecum and proximal colon of their hosts causing the human disease, trichuriasis. Trichuriasis is characterized by colitis attributed to the inflammatory response elicited by the parasite while tunnelling through intestinal epithelial cells (IECs). The IL-10 family of receptors, comprising combinations of subunits IL-10Rα, IL-10Rβ, IL-22Rα and IL-28Rα, modulates intestinal inflammatory responses. Here we carefully dissected the role of these subunits in the resistance of mice to infection with T. muris, a mouse model of the human whipworm T. trichiura. Our findings demonstrate that whilst IL-22Rα and IL-28Rα are dispensable in the host response to whipworms, IL-10 signalling through IL-10Rα and IL-10Rβ is essential to control caecal pathology, worm expulsion and survival during T. muris infections. We show that deficiency of IL-10, IL-10Rα and IL-10Rβ results in dysbiosis of the caecal microbiota characterised by expanded populations of opportunistic bacteria of the families Enterococcaceae and Enterobacteriaceae. Moreover, breakdown of the epithelial barrier after whipworm infection in IL-10, IL-10Rα and IL-10Rβ-deficient mice, allows the translocation of these opportunistic pathogens or their excretory products to the liver causing organ failure and lethal disease. Importantly, bone marrow chimera experiments indicate that signalling through IL-10Rα and IL-10Rβ in haematopoietic cells, but not IECs, is crucial to control worm expulsion and immunopathology. These findings are supported by worm expulsion upon infection of conditional mutant mice for the IL-10Rα on IECs. Our findings emphasize the pivotal and complex role of systemic IL-10Rα signalling on immune cells in promoting microbiota homeostasis and maintaining the intestinal epithelial barrier, thus preventing immunopathology during whipworm infections.
鞭虫 Trichuris trichiura 是一种土壤传播的寄生虫，栖息在其宿主的盲肠和近端结肠的上皮细胞中，导致人类疾病——鞭虫病。鞭虫病的特征是结肠炎，这归因于寄生虫在穿过肠上皮细胞（IECs）时引起的炎症反应。IL-10 家族受体由 IL-10Rα、IL-10Rβ、IL-22Rα 和 IL-28Rα 亚单位组合而成，调节肠道炎症反应。在这里，我们仔细研究了这些亚单位在抵抗感染 T. muris 的小鼠中的作用，T. muris 是人类鞭虫 T. trichiura 的小鼠模型。我们的研究结果表明，虽然 IL-22Rα 和 IL-28Rα 在宿主对鞭虫的反应中是可有可无的，但 IL-10 通过 IL-10Rα 和 IL-10Rβ 的信号传导对于控制盲肠病理学、蠕虫排出和 T. muris 感染期间的生存是必不可少的。我们表明，缺乏 IL-10、IL-10Rα 和 IL-10Rβ 会导致盲肠微生物组的失调，其特征是机会性细菌属的丰度增加，包括肠球菌科和肠杆菌科。此外，在 IL-10、IL-10Rα 和 IL-10Rβ 缺陷小鼠中，鞭虫感染后上皮屏障的破坏，使这些机会性病原体或其排泄产物易位到肝脏，导致器官衰竭和致命疾病。重要的是，骨髓嵌合体实验表明，在造血细胞中而不是在 IEC 中通过 IL-10Rα 和 IL-10Rβ 进行信号传导对于控制蠕虫排出和免疫病理学至关重要。这些发现得到了感染条件性突变小鼠的实验支持，这些突变小鼠的 IEC 上缺乏 IL-10Rα。我们的研究结果强调了系统性 IL-10Rα 信号在免疫细胞上的关键和复杂作用，它促进了微生物组的动态平衡并维持了肠道上皮屏障，从而防止了鞭虫感染期间的免疫病理学。
