MUC1 cell surface mucin is a critical element of the mucosal barrier to infection

Abstract

Cell surface mucin glycoproteins are highly expressed by all mucosal tissues, yet their physiological role is currently unknown. We hypothesized that cell surface mucins protect mucosal cells from infection. A rapid progressive increase in gastrointestinal expression of mucin 1 (Muc1) cell surface mucin followed infection of mice with the bacterial pathogen Campylobacter jejuni. In the first week following oral infection, C. jejuni was detected in the systemic organs of the vast majority of Muc1 -/-mice but never in Muc1 +/+ mice. Although C. jejuni entered gastrointestinal epithelial cells of both Muc1 -/-and Muc1 +/+ mice, small intestinal damage as manifested by increased apoptosis and enucleated and shed villous epithelium was more common in Muc1 -/-mice. Using radiation chimeras, we determined that prevention of systemic infection in wild-type mice was due exclusively to epithelial Muc1 rather than Muc1 on hematopoietic cells. Expression of MUC1-enhanced resistance to C. jejuni cytolethal distending toxin (CDT) in vitro and CDT null C. jejuni showed lower gastric colonization in Muc1 -/-mice in vivo. We believe this is the first in vivo experimental study to demonstrate that cell surface mucins are a critical component of mucosal defence and that the study provides the foundation for exploration of their contribution to epithelial infectious and inflammatory diseases.

The cell surface mucin MUC1 limits the severity of influenza A virus infection

“…One explanation is that IAV binding to MUC1 may trigger release of the extracellular domain prior to its internalization. This ''releasable decoy'' mechanism is similar to what we have previously proposed for protection against C. jejuni infection in the gastrointestinal tract 24 and our experiments indicating MUC1 is shed into the culture supernatant of PR8-infected CHO-K1 MUC1 þ cells would support this function for influenza virus as well.…”

“…39 The towering structure of the MUC1 extracellular domain, estimated to be 200-500 nm in length when fully glycosylated, 21 plus expression of an abundance of terminally linked Neu5Ac is a likely first point of contact for HA binding by IAV that has penetrated the overlying gel mucus layer and gained access to the epithelial cell surface. Such chemoattraction and adherence to specific mucin carbohydrates have also been demonstrated for mouse adenovirus type I (MAVS-1) 40 and respiratory syncytial virus (RSV), 13 as well as bacteria including Campylobacter jejuni, 24 Helicobacter pylori 26 and Pseudomonas aeruginosa. 25 In this study we have been able to block IAV infection of MDCK cells with synthetic MUC1 glycopeptides expressing a2-6-linked Neu5Ac, with those having a longer peptide chain of 20 amino acids being much more efficient than glycopeptides of 11 amino acids in length.…”

“…Initially, the large extracellular domain, which is heavily O-glycosylated with oligosaccharide structures terminating in Neu5Ac, acts as a virus trap and a releasable decoy ligand for IAV, resulting in partial dampening of infection during the early stages. Second, we contend that, as observed for other pathogens, [24][25][26] MUC1 regulates influenza virus-induced inflammation that would otherwise contribute to more severe pulmonary disease and potentially death. Understanding the MUC1 regulatory mechanisms in the context of IAV infection is of obvious interest to our future studies and may lead to an understanding of the mechanism as to why IAV infection is as a major trigger for disease exacerbations in patients with chronic respiratory illnesses where cs-mucins are aberrantly expressed.…”

“…As many microbial pathogens are known to trigger shedding of the MUC1 extracellular domain (ED) after binding, [24][25][26][27] we tested whether this phenomenon could also be caused by IAV. Supernatants were collected from PR8-infected CHO-K1 control and MUC1 þ cell cultures and the amount of MUC1-ED present in the supernatant was determined by ELISA.…”

Mucin 1 is a novel glycoprotein involved in host defense against invasive pneumococcal disease

“…11,20 In this sense, MUC1 protects against bacterial infection by Helycobacter pylori and Campylobacter jejuni. 21,22 The fact that MUC1 plays critical roles in protection against a diverse variety of important human bacterial pathogens affecting different locations of the host including the respiratory tract and the gastrointestinal barrier, demonstrate the importance of this molecule in host defense. Further research in this field is necessary as it could lead to the development of novel strategies to prevent or reduce the impact of infectious diseases affecting host sites that are continuously exposed to microbial intruders such as the airway and the gastrointestinal tract.…”