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Liang, Qiaochu

University of British Columbia

The intestinal mucus layer is an essential structure that is well recognized, not only as a key physiochemical barrier that limits direct contact between noxious agents within the intestinal lumen and the underlying epithelium, but also as an important interface between the resident gut microbiota and the host. Mucus is primarily comprised of the mucin (Muc)-2 protein, that is heavily O-glycosylated by five major sugar monomers, including sialic acid. To establish infections, enteric pathogens must evolve strategies to adapt to the intestinal environment, overcome the mucus barrier and microbiota-mediated colonization resistance to successfully infect their hosts. I investigated the interactions between the pathogen and mucus, as well as the mucus-degrading commensals during Citrobacter rodentium infection. C. rodentium is an attaching and effacing pathogen that must cross the colonic mucus layer to infect intestinal epithelial cells (IEC). I demonstrated that upon entering the host, C. rodentium localized to the colonic mucus layer and required mucin-derived sialic acid to fuel its growth and virulence. A C. rodentium strain deficient in sialic acid uptake (ΔnanT) was dramatically impaired in infecting mice. Sensing of sialic acid also enabled the pathogen to migrate towards mucus and promoted C. rodentium’s virulence by inducing the secretion of two key virulence factors, which enhanced the translocation across the mucus layer and increased adhesion to the epithelium. Mucus-degrading commensal bacteria mediated C. rodentium’s access to sialic acid by releasing sialic acid from mucin glycans. Correspondingly, the intestines of germ-free (GF) mice contained very low levels of free sialic acid and in line with this, C. rodentium displayed impaired virulence when infecting them. However, mice mono-colonized with the commensal bacterium Bacteroides thetaotaomicron that can readily degrade mucin glycans displayed increased susceptibility to C. rodentium colonic infection. Overall, my research contributes to a better understanding of how enteric bacterial pathogens interact with mucin glycans, and further emphasizes the crucial role played by mucin-degrading microbiota in enabling these interactions.

Text

2023-09-05

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85794

Experimental Medicine

University of British Columbia

UBCV

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