Date Published: January 14, 2019
Publisher: Public Library of Science
Author(s): María A. Duque-Correa, Natasha A. Karp, Catherine McCarthy, Simon Forman, David Goulding, Geetha Sankaranarayanan, Timothy P. Jenkins, Adam J. Reid, Emma L. Cambridge, Carmen Ballesteros Reviriego, Werner Müller, Cinzia Cantacessi, Gordon Dougan, Richard K. Grencis, Matthew Berriman, Nicola Harris.
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.
A single layer of intestinal epithelial cells (IECs) in conjunction with the overlaying mucus acts as a primary barrier to viruses, bacteria and parasites entering the body via the gastrointestinal tract . Paradoxically, the intestinal epithelium is also the host tissue for diverse pathogens including intestinal parasitic worms [2, 3]. Amongst the intestinal worms, whipworms (Trichuris trichiura) infect hundreds of millions of people and cause trichuriasis, a major Neglected Tropical Disease [4, 5].
We have shown that upon infection with whipworms, signalling by IL-10, but not IL-22 or IL-28, is crucial for the resistance to colonization by opportunistic pathogens, control of host inflammation, intestinal barrier maintenance and worm expulsion. We dissected the contribution of the IL-10 cytokine and the subunits of its cognate receptor and observed that lack of any of the components resulted in the development of a chronic whipworm infection that led to unsustainable pathology, confirming previous reports [8, 20, 21] and extending the observations to deficiency of the IL-10Rβ chain.