Immune-driven alterations in mucin sulphation is an important mediator of Trichuris muris helminth expulsion.

Sumaira Z. Hasnain,Hui Tong,Richard K. Grencis,David J. Thornton,Michael A. McGuckin,Rohan Lourie,Paul A. Dawson,Peter Hutson,Edward Mitre

doi:10.1371/journal.ppat.1006218

Abstract

Mucins are heavily glycosylated proteins that give mucus its gel-like properties. Moreover, the glycans decorating the mucin protein core can alter the protective properties of the mucus barrier. To investigate whether these alterations could be parasite-induced we utilized the Trichuris muris (T. muris) infection model, using different infection doses and strains of mice that are resistant (high dose infection in BALB/c and C57BL6 mice) or susceptible (high dose infection in AKR and low dose infection in BALB/c mice) to chronic infection by T. muris. During chronicity, within the immediate vicinity of the T. muris helminth the goblet cell thecae contained mainly sialylated mucins. In contrast, the goblet cells within the epithelial crypts in the resistant models contained mainly sulphated mucins. Maintained mucin sulphation was promoted by TH2-immune responses, in particular IL-13, and contributed to the protective properties of the mucus layer, making it less vulnerable to degradation by T. muris excretory secretory products. Mucin sulphation was markedly reduced in the caecal goblet cells in the sulphate anion transporter-1 (Sat-1) deficient mice. We found that Sat-1 deficient mice were susceptible to chronic infection despite a strong TH2-immune response. Lower sulphation levels lead to decreased efficiency of establishment of T. muris infection, independent of egg hatching. This study highlights the complex process by which immune-regulated alterations in mucin glycosylation occur following T. muris infection, which contributes to clearance of parasitic infection.

Highlights

The intestinal epithelium is lined by a continuous mucus barrier which provides physical protection and chemically protects the epithelial cell layer by sequestering important host defence factors within its complex matrix [1]
2 billion people are infected with worms every year, causing physical, nutritional and cognitive impairment in children
It was shown that a reduction in mucin sulphation, in particular, can lead to an increase in susceptibility to Immune-driven alterations in mucin sulphation is an important mediator of helminth expulsion colitis and bacterial infections [24]

Summary

Introduction

The intestinal epithelium is lined by a continuous mucus barrier which provides physical protection and chemically protects the epithelial cell layer by sequestering important host defence factors within its complex matrix [1]. The Olinked sugars are assembled progressively by glycosyltransferases on to a serine or threonine residue, found in the serine-threonine-proline rich tandem repeat regions of the mucin protein core [1]. These glycan chains have well-established fundamental roles in many biological processes including in inflammatory responses [4]. Changes in mucin glycosylation have been previously described in murine parasitic infections. Whether these changes are important in the protective function of the mucus barrier, has not yet been established. Mice lacking either core 1- or core 3-derived O-glycan chains, or both, develop spontaneous colitis with the double knockout mice having the most severe and widespread disease [15,16,17]

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