Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infectionCitation formats

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Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infection. / Sanger Mouse Genetics Project.

In: PLoS Pathogens, Vol. 15, No. 1, 14.01.2019, p. e1007265.

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Sanger Mouse Genetics Project. / Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infection. In: PLoS Pathogens. 2019 ; Vol. 15, No. 1. pp. e1007265.

Bibtex

@article{2a1e5a222f014ab98ee9d3c3135208f4,
title = "Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infection",
abstract = "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.",
author = "{Sanger Mouse Genetics Project} and Duque-Correa, {Mar{\'i}a A} and Karp, {Natasha A} and Catherine McCarthy and Simon Forman and David Goulding and Geetha Sankaranarayanan and Jenkins, {Timothy P} and Reid, {Adam J} and Cambridge, {Emma L} and {Ballesteros Reviriego}, Carmen and Werner M{\"u}ller and Cinzia Cantacessi and Gordon Dougan and Grencis, {Richard K} and Matthew Berriman",
year = "2019",
month = "1",
day = "14",
doi = "10.1371/journal.ppat.1007265",
language = "English",
volume = "15",
pages = "e1007265",
journal = "PL o S Pathogens",
issn = "1553-7374",
publisher = "Public Library of Science",
number = "1",

}

RIS

TY - JOUR

T1 - Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infection

AU - Sanger Mouse Genetics Project

AU - Duque-Correa, María A

AU - Karp, Natasha A

AU - McCarthy, Catherine

AU - Forman, Simon

AU - Goulding, David

AU - Sankaranarayanan, Geetha

AU - Jenkins, Timothy P

AU - Reid, Adam J

AU - Cambridge, Emma L

AU - Ballesteros Reviriego, Carmen

AU - Müller, Werner

AU - Cantacessi, Cinzia

AU - Dougan, Gordon

AU - Grencis, Richard K

AU - Berriman, Matthew

PY - 2019/1/14

Y1 - 2019/1/14

N2 - 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.

AB - 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.

U2 - 10.1371/journal.ppat.1007265

DO - 10.1371/journal.ppat.1007265

M3 - Article

VL - 15

SP - e1007265

JO - PL o S Pathogens

JF - PL o S Pathogens

SN - 1553-7374

IS - 1

ER -