Approaches to Enhancing Mucus Production to Counteract Infection

Abstract

Mucosal surfaces are covered with mucus that protects the underlying epithelium from pathogens and particles. As the primary routes through which pathogens enter the host, mucosal surfaces rely on this mucus layer as a critical first line of defense. Mucins - highly O-glycosylated glycoproteins - are synthesized and secreted by mucous and goblet cells, and they play key roles in pathogen binding, clearance, and modulation of microbial growth and virulence. Helicobacter pylori is the most common gastric pathogen, it is associated with chronic inflammation of the gastric mucosa, and in some cases progression to gastric adenocarcinoma. While H. pylori can attach to gastric epithelial cells, it predominantly resides within the mucus layer where it interacts with mucins. Similarly, Aeromonas salmonicida is an opportunistic pathogen responsible for furunculosis in rainbow trout and other fish. Mucins can bind to A. salmonicida and regulate its growth. In this thesis, I investigated the use of compounds known to affect mucin production to enhance and restore mucin biosynthesis and assessed how these changes influence pathogen localization and host inflammation. Mice infected with H. pylori were treated with Interleukin-4, (R)-α-methylhistamine, Rebamipide, Roxatidine, or a combination of the latter two compounds. These treatments exhibited gastroprotective effects by reducing inflammation scores. Using metabolic labeling by GalNAz incorporation, we observed increased mucin biosynthesis following treatments. This increase in mucin biosynthesis correlated with a reduction in H. pylori colonization in the gastric pits. In rainbow trout, lipopolysaccharide treatment resulted in an increased mucin production in the stomach and intestine. Furthermore, mucins isolated from rainbow trout regulated A. salmonicida virulence and reduced the bacterium’s ability to auto-aggregate. These findings suggest that targeting mucosal surfaces to enhance mucin biosynthesis represents a promising strategy to counteract infections caused by mucosal pathogens such as H. pylori and A. salmonicida. However, further research is necessary to elucidate the regulatory mechanisms of mucin production and secretion, as well as to better understand the functional characteristics of the secreted mucus.