Abstract
The polymeric mucin component of the intestinal mucus barrier changes during nematode infection to provide not only physical protection but also to directly affect pathogenic nematodes and aid expulsion. Despite this, the direct interaction of the nematodes with the mucins and the mucus barrier has not previously been addressed. We used the well-established Trichuris muris nematode model to investigate the effect on mucins of the complex mixture of immunogenic proteins secreted by the nematode called excretory/secretory products (ESPs). Different regimes of T. muris infection were used to simulate chronic (low dose) or acute (high dose) infection. Mucus/mucins isolated from mice and from the human intestinal cell line, LS174T, were treated with ESPs. We demonstrate that serine protease(s) secreted by the nematode have the ability to change the properties of the mucus barrier, making it more porous by degrading the mucin component of the mucus gel. Specifically, the serine protease(s) acted on the N-terminal polymerising domain of the major intestinal mucin Muc2, resulting in depolymerisation of Muc2 polymers. Importantly, the respiratory/gastric mucin Muc5ac, which is induced in the intestine and is critical for worm expulsion, was protected from the depolymerising effect exerted by ESPs. Furthermore, serine protease inhibitors (Serpins) which may protect the mucins, in particular Muc2, from depolymerisation, were highly expressed in mice resistant to chronic infection. Thus, we demonstrate that nematodes secrete serine protease(s) to degrade mucins within the mucus barrier, which may modify the niche of the parasite to prevent clearance from the host or facilitate efficient mating and egg laying from the posterior end of the parasite that is in intimate contact with the mucus barrier. However, during a TH2-mediated worm expulsion response, serpins, Muc5ac and increased levels of Muc2 protect the barrier from degradation by the nematode secreted protease(s).
Highlights
Immune mediated elimination of gastrointestinal (GI) parasitic nematodes has been a subject of considerable investigation [1]
The gel-like material that blankets the surface of the intestine, forms a protective barrier that is an important part of our innate immune system
We unravel that worm products are unable to degrade forms of mucins present in the mucus barrier during worm expulsion, suggesting that these enzymes may be released by the worm as part of its regime to improve its niche and survival in the host
Summary
Immune mediated elimination of gastrointestinal (GI) parasitic nematodes has been a subject of considerable investigation [1]. Until recently, definition of the precise role of goblet cells in host protection remained elusive, especially with regards to the major secreted component of goblet cells, the mucins, which are pivotal to the formation of the mucus layer that overlies the intestinal epithelium. Using established gastrointestinal nematode models Trichuris muris, Trichinella spiralis and Nippostrongylus brasiliensis, we have recently demonstrated that mucins are critical in resolving infection [3,4,5]. The major intestinal mucin Muc plays a significant role in the concerted protective worm expulsion mechanism and in its absence T. muris expulsion is significantly delayed [4]. The Muc5ac mucin, not usually expressed in the murine intestine but induced post-infection during a TH2-type immune response, was demonstrated to be necessary for intestinal worm clearance [3]
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