The influence of mucin glycans on microbial virulence and competition

Abstract

The human body is colonized by trillions of microbes, many of which reside in a layer of mucus that covers all wet epithelia in the body. In this way, mucus serves as the first line of defense to the host, simultaneously protecting against pathogens while providing a habitat where commensal microbes thrive. It has long been known that defects in mucus production or biochemistry are associated with opportunistic infections; however, few studies have focused on how components of the intact mucus barrier interact with resident microbes to promote health. In this thesis, I fill this gap using a clinically relevant 3-dimensional model of the mucus environment based on mucin glycoproteins, the major structural component of mucus. This in vitro culturing system mimics the natural mucus environment, where mucin polymer domains interact and entangle into a flexible hydrogel, as opposed to 2-dimensional surface coatings, which can create artificially concentrated amounts of surface mucins. I apply this system to answer three major conceptual questions, separated into three projects. In the first project, I study the ability of mucin and their attached glycans to regulate interactions between a clinically-important opportunistic pathogen, Pseudomonas aeruginosa, and its host. I then investigate the underlying genetic mechanisms that enable P. aeruginosa to sense and respond to the mucus environment, and explore how mucin glycan-sensing in turn impacts microbe-microbe interactions in the mucosal niche. I end by investigating how mucin glycan-mediated microbial regulation modulates the composition of complex microbial communities isolated from the human oral cavity. Collectively, the work presented in this thesis lays the framework for characterizing the therapeutic nature of mucin and how specific mucin glycan moieties modulate the behavior, pathogenicity, and competitive interactions of host-associated microbes.