Muc5ac: a critical component mediating the rejection of enteric nematodes

Abstract

The mucin Muc5ac is essential for the expulsion of Trichuris muris and other gut-dwelling nematodes.

A sticky end for gastrointestinal helminths; the role of the mucus barrier

“…Perhaps surprisingly, ablation of Muc2 in vivo only led to a delayed T. muris expulsion during acute infection, even though a Th2‐mediated immune response prevailed 73. Further studies showed there was an induction of the polymeric mucin Muc5ac, normally a gastric and lung mucin, which was important for T. muris parasite expulsion and suggested a protective function for this mucin in the intestine 9. This was confirmed using Muc5ac‐deficient mice, which were completely susceptible to T. muris infection unlike their wild‐type counterparts.…”

“…Importantly, the susceptible phenotype was not reversed even after administration of anti‐IFN‐γ to skew the Th1 dominated environment generated in chronic infection towards a Th2‐directed immune response, normally associated with resistance 10. Importantly, there was an induction of Muc5ac transcripts in T. suis infected pigs, suggesting a protective role across species,74 and there is data to suggest that Muc5ac may also have a broad antihelminth action as Muc5ac null mice were also impaired in their ability to efficiently expel N. brasiliensis and T. spiralis 9…”

“…However, the focus of this review will be the major component of the intestinal mucus gel, the secreted polymeric mucin, MUC2 23. It is noteworthy that MUC5AC expression can be induced within the intestine during foetal development, adenocarcinoma inflammatory bowel disease, and of specific relevance to this review, during helminth infection 9, 24, 25, 26…”

“…Indeed, subsequent characterization of animal models for GI helminth infections and the development of protocols to assess mucosal barrier properties have allowed the development of robust systems to directly investigate aspects of mucus barrier function and properties in vivo. These studies have demonstrated that mucins and mucus‐associated proteins hold key roles in altering the intestinal niche to enhance parasite expulsion, thus contributing to immune‐mediated host protection 9, 10, 11. Further insight into the precise functional role(s) that mucins and mucus‐associated proteins play within the mucus barrier may uncover potential avenues for novel therapeutic targets to eradicate this group of important neglected tropical diseases.…”

Immunity to gastrointestinal nematode infections

“…171 Consistent with these data, Muc5ac is only upregulated in resistant mouse strains 170 and Muc5ac-deficient mice have impaired expulsion of T. muris, N. brasiliensis, and T. spiralis. 173 Increased mucus production and the mucin switch are largely driven by IL-13, 173 IL-4, 174 and IL-22, 175 but the principle of physical obstruction provided by mucus layers can also be extended to other mucosal sites such as the lungs where the lectin surfactant protein-D, which acts as a lubricant, is needed for optimal protection against the pulmonary stage of N. brasiliensis infection. 176 Another expulsion mechanism is the release of various proteins by activated granulocytes and epithelial cells, most of which are toxic to parasites.…”