AbstractThe whipwormTrichuris trichiurais 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 withT. muris,a mouse model of the human whipwormT. 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 duringT. murisinfections. 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 role of systemic IL-10Rα signalling on immune cells in promoting microbiota homeostasis and maintaining the intestinal epithelial barrier, thus preventing immunopathology during whipworms infections.Author summaryThe human gut is home to millions of bacteria, collectively called the microbiota, and also to parasites that include whipworms. The interactions between gut cells, the microbiota and whipworms define conditions for balanced parasitism. Cells lining the gut host whipworms but also interact with gut immune cells to deploy measures that control or expel whipworms whilst maintaining a barrier to prevent microbial translocation. Whipworms affect the composition of the microbiota, which in turn impacts the condition of the gut lining and the way in which immune cells are activated. In order to avoid tissue damage and disease, these interactions are tightly regulated. Here we show that signalling through a member of the IL-10 receptor family, IL-10Rα, in gut immune cells is critical for regulating of these interactions. Lack of this receptor on gut immune cells results in persistence of whipworms in the gut accompanied by an uncontrolled inflammation that destroys the gut lining. This tissue damage is accompanied by the overgrowth of members of the microbiota that act as opportunistic pathogens. Furthermore, the destruction of the gut barrier allows these bacteria to reach the liver where they cause organ failure and fatal disease.
Chemokine receptor trafficking coordinates neutrophil clustering and dispersal at wounds in zebrafish
