Mucin Gene Deficiency in Mice Impairs Host Resistance to an Enteric Parasitic Infection

Abstract

Background & AimsHyperplasia of mucin-secreting intestinal goblet cells accompanies a number of enteric infections, including infections by nematode parasites. Nevertheless, the precise role of mucins in host defense in nematode infection is not known. We investigated the role of the mucin (Muc2) in worm expulsion and host immunity in a model of nematode infection.MethodsResistant (BALB/c, C57BL/6), susceptible (AKR), and Muc2-deficient mouse strains were infected with the nematode, Trichuris muris, and worm expulsion, energy status of the whipworms, changes in mucus/mucins, and inflammatory and immune responses were investigated after infection.ResultsThe increase in Muc2 production, observed exclusively in resistant mice, correlated with worm expulsion. Moreover, expulsion of the worms from the intestine was significantly delayed in the Muc2-deficient mice. Although a marked impairment in the development of periodic acid Schiff (PAS)–stained intestinal goblet cells was observed in Muc2-deficient mice, as infection progressed a significant increase in the number of PAS-positive goblet cells was observed in these mice. Surprisingly, an increase in Muc5ac, a mucin normally expressed in the airways and stomach, was observed after infection of only the resistant animals. Overall, the mucus barrier in the resistant mice was less permeable than that of susceptible mice. Furthermore, the worms isolated from the resistant mice had a lower energy status.ConclusionsMucins are an important component of innate defense in enteric infection; this is the first demonstration of the important functional contribution of mucins to host protection from nematode infection.

Immunity to gastrointestinal nematode infections

“…171 In addition, the host can produce serine-protease inhibitors that prevent further loss of mucin 2. 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.…”

“…Ejection of gastrointestinal nematodes relies on a combination of physiological mechanisms that include enhanced mucus secretion by goblet cells, release of neutralizing proteins by granulocytes and epithelial cells, epithelial hyperproliferation, and increased intestinal peristalsis (Figure 1c), perhaps the most important of which is augmented production of mucins. Mucins trap worms by impeding motility, and hence mice lacking mucin 2 (the predominant glycoprotein of the mucus layer) are rendered susceptible to T. muris infection and show delayed worm expulsion, 170 illustrating the importance of this barrier. Nonetheless, T. muris and other nematode larvae are still able to penetrate the mucus layer of mucin-proficient mice upon infection, indicating that they have evolved strategies to circumvent this barrier.…”

Overexpressing mouse model demonstrates the protective role of Muc5ac in the lungs

“…Muc1-deficient mice are less resistant to Helicobacter pylori colonization than control littermates and develop a severe subsequent gastritis (41). Muc2-deficient mice spontaneously develop colitis (35) and have impaired resistance against enteric infection (42).…”

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

“…The secretion of MUC2 can be influenced by a broad range of mediators including cytokine signals, microbial‐derived products, adrenocorticotropic hormones, autophagic proteins, reactive oxygen species and components of the inflammasome (NOD‐, LRR‐ and pyrin domain‐containing 6) 10, 11, 42, 43, 44, 45, 46…”

“…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.…”