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Mucus-bacteria interactions in the gut : investigating the role of the mucin Muc2 and its glycosylation in host defense during enteric bacterial infections

University of British Columbia

The intestinal mucus layer, which is largely composed of the secreted mucin Muc2 provides a first line of defense in the intestine. Muc2 is a heavily O-glycosylated protein with core 1 and core 3 derived O-glycans as primary constituents. It plays an important role in host defense against the attaching/effacing (A/E) pathogen Citrobacter rodentium. However whether it provides protection against the invasive human pathogen Salmonella is still unclear. Furthermore, the role of O-glycosylation in mediating the protective role played by the Muc2 mucin against enteric pathogens has not been investigated. Likewise, although almost all enteric bacterial pathogens must cross the overlying mucus layer to infect the intestinal epithelium, there is very little known about mucus-enteric bacterial interactions and virulence strategies used to accomplish this feat. We began our investigations by comparing Salmonella-induced colitis and mucus dynamics in Muc2-deficient (Muc2 -/-), C3GnT -/-, and C57BL/6 (WT) mice. While absence of core 3 derived O-glycosylation only impacted epithelial barrier integrity, absence of Muc2 resulted in significantly higher barrier disruption, host mortality rates, and increased colonic and systemic Salmonella burdens. Likewise, absence of core 1 derived O-glycans (C1galt1 -/- mice) resulted in heightened susceptibility to C. rodentium, characterized by impaired mucus levels in the lumen, and bacterial aggregation in close proximity to the intestinal epithelial surface, phenotypes not seen in WT or C3GnT -/- counterparts. To understand if the non-motile pathogen C. rodentium used bacterial proteases/mucinases as a mucus degrading strategy to gain access to the underlying epithelium, we investigated the role of a putative mucinase and a class 2 SPATE PicC. While PicC did not affect C. rodentium’s ability to colonize the colon, it appeared to have an unprecedented role in regulating C. rodentium’s activation of the innate receptor TLR2, suggesting that despite its mucinase activity, PicC's major roles in vivo may be to limit C. rodentium aggregation and its recognition by the host's innate immune system. Overall these studies highlight a novel protective role of Muc2 and its O-linked glycosylation in host defense against enteric infections and the importance of Muc2-mediated regulation of pathogen burdens at the intestinal epithelial surface.

Text

2017-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/57682

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/