Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infection.
Karp, Natasha A
Reid, Adam J
Cambridge, Emma L
Ballesteros Reviriego, Carmen
Sanger Mouse Genetics Project,
Grencis, Richard K
Public Library of Science (PLoS)
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Duque-Correa, M. A., Karp, N. A., McCarthy, C., Forman, S., Goulding, D., Sankaranarayanan, G., Jenkins, T., et al. (2019). Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infection.. PLoS pathogens, 15 (1), e1007265. https://doi.org/10.1371/journal.ppat.1007265
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-10R, IL-10R, IL-22R and IL-28R, 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-22R and IL-28R are dispensable in the host response to whipworms, IL-10 signalling through IL-10R and IL-10R is essential to control caecal pathology, worm expulsion and survival during T. muris infections. We show that deficiency of IL-10, IL-10R and IL-10R 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-10R and IL-10R-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-10R and IL-10R 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-10R on IECs. Our findings emphasize the pivotal and complex role of systemic IL-10R signalling on immune cells in promoting microbiota homeostasis and maintaining the intestinal epithelial barrier, thus preventing immunopathology during whipworm infections.
Sanger Mouse Genetics Project, 3i consortium, Intestines, Animals, Mice, Inbred C57BL, Mice, Trichuris, Trichuriasis, Disease Models, Animal, Interleukins, Interleukin-10, Cytokines, Signal Transduction, Homeostasis, Receptors, Interleukin-10, Gastrointestinal Microbiome
External DOI: https://doi.org/10.1371/journal.ppat.1007265
This record's URL: https://www.repository.cam.ac.uk/handle/1810/288327
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/