The major secreted protein of the whipworm parasite tethers to matrix and inhibits interleukin-13 function

Infection by soil transmitted parasitic helminths, such as Trichuris spp, are ubiquitous in humans and animals but the mechanisms determining persistence of chronic infections are poorly understood. Here we show that p43, the single most abundant protein in T. murisexcretions/secretions, is non-immunogenic during infection and has an unusual sequence and structure containing subdomain homology to thrombospondin type 1 and interleukin (IL)−13 receptor (R) α2. Binding of p43 to IL-13, the key effector cytokine responsible for T. muris expulsion, inhibits IL-13 function both in vitro and in vivo. Tethering of p43 to matrix proteoglycans presents a bound source of p43 to facilitate interaction with IL-13, which may underpin chronic intestinal infection. Our results suggest that exploiting the biology of p43 may open up new approaches to modulating IL-13 function and control of Trichuris infections.

Allison J. Bancroft1,2,3,4, Colin W. Levy5, Thomas A. Jowitt2,4, Kelly S. Hayes1,2,3,4, Seona Thompson1,2,3,4, Edward A. Mckenzie5, Matthew D. Ball5, Eamon Dubaissi1,2,3,4, Aidan P. France5, Bruno Bellina5, Catherine Sharpe1,2,3,4, Aleksandr Mironov4, Sheila L. Brown1,3,4,6, Peter C. Cook 1,3,4,6,
Andrew S. MacDonald 1,3,4,6, David J. Thornton 1,2,3,4 & Richard K. Grencis1,2,3,4

1 Lydia Becker Institute for Immunology and Inflammation, Manchester M13 9PT, UK. 2Wellcome Trust Centre for Cell Matrix Research, Manchester M13 9PT, UK. 3Division of Infection, Immunity and Respiratory Medicine, Manchester M13 9PT, UK. 4 School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK. 5 Manchester Institute of Biotechnology, University of Manchester, 3.020 Garside Building, 131 Princess Street, Manchester M1 7DN, UK. 6 Manchester Collaborative Centre for Inflammation
Research, Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Core Technology, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK. Correspondence and requests for materials should be addressed to A.J.B. (email: allison.j.bancroft@manchester.ac.uk) or to R.K.G. (email: Richard.Grencis@manchester.ac.uk)

https://www.nature.com/articles/s41467-019-09996-z.pdf

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