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The role of colonic goblet cells in host defense against attaching and effacing bacterial pathogens Bergstrom, Kirk S. B.

Abstract

The non-invasive attaching and effacing (A/E) pathogens Enteropathogenic and Enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively) are a prominent subgroup of diarrheagenic E. coli, and remain an important cause of morbidity and mortality worldwide. A/E pathogens intimately attach to the surface of intestinal epithelial cells, and efface or destroy their microvilli. The intestinal epithelium is the first line of defense against A/E and all pathogens, and evidence is implicating epithelial secretory cells as playing a key role in this regard. Goblet cells are specialized secretory epithelial cells that are the sole producers of the mucus barrier lining the intestinal tract through the release of the polymeric Muc2 mucin. Goblet cells also secrete the small peptide Resistin-like Molecule-{beta} (RELMβ), which plays a direct role in host defense against parasitic helminths. Despite the abundance of which these molecules are released, little is known of their role in host-protection against A/E pathogens. I hypothesized that goblet cells play a critical role in host defense against A/E bacteria by secretion of Muc2/mucus and RELMβ into the intestinal tract. Using Citrobacter rodentium, a murine A/E pathogen that is an established model of EPEC and EHEC, my results demonstrate that goblet cells are a critical component of innate host-defense against an A/E pathogen. Studies with Muc2⁻/⁻ mice show that Muc2/mucus production was critical for limiting luminal burdens, and for flushing away pathogenic bacteria as well as commensal bacteria from the mucosa. Moreover, RELMβ was highly induced and secreted into the lumen during the first week of infection. Studies with Retnlb⁻/⁻ mice demonstrated that RELMβ production limited cecal burdens, deep penetration of colonic crypts, and severe inflammatory damage following infection. Lastly, adaptive immunity plays a role in modulating goblet cell function, by promoting a down-regulation of goblet cell-specific gene expression and protein production, including Muc2. This effect appears to reflect a generalized adaptive immunity-mediated epithelial proliferative response and is associated with clearance of surface-associated pathogens. Thus, goblet cells are critical for managing infection by an A/E bacterial pathogen. These studies highlight a novel and previously unappreciated function of goblet cells in host defense against enteric bacterial infection.

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