Mucin and mucin glycans alter behaviorof mucosal pathogens
The majority of the microorganisms that colonize the human body, collectively the human microbiota, reside within the mucus layer. While mucus hydrates and lubricates host tissues, it also serves as a protective barrier. Mucus physically blocks pathogens and other microorganisms from reaching host c...
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| Format: | Thesis |
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Massachusetts Institute of Technology
2022
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| Online Access: | https://hdl.handle.net/1721.1/144637 https://orcid.org/0000-0002-0605-1971 |
| Summary: | The majority of the microorganisms that colonize the human body, collectively the human microbiota, reside within the mucus layer. While mucus hydrates and lubricates host tissues, it also serves as a protective barrier. Mucus physically blocks pathogens and other microorganisms from reaching host cells; however, mucus additionally decreases the virulence of certain opportunistic pathogens to prevent infections. A greater understanding of mucus’ spectrum of activity could lead to future therapeutics, especially important as the threat of antimicrobial resistance increases. In this thesis, I investigate mucus’ ability to block infections by two bacterial pathogens, one opportunistic and one primary. To isolate the important factors of mucus, I utilize a three-dimensional mucus model composed of natively purified mucin polymers, the major gel-forming component of mucus. With this system, I can disentangle the effects of mucin from the rest of mucus, such as other proteins and salts. I first explore mucin’s impact on Klebsiella pneumoniae, an often multi-drug resistant and sometimes hypervirulent bacterium. I determine that mucin decreases K. pneumoniae surface attachment and biofilm formation, major sources of persistent and antimicrobial tolerant infections especially on implanted medical devices. Additionally, I discover that the glycans cleaved from the mucin protein backbone also block K. pneumoniae attachment to abiotic surfaces, suggesting the possibility of mucin mimetics to prevent biofilm formation on medical devices. My second project examines the primary pathogen Salmonella enterica serovar Typhimurium, which must pass through the mucus barrier before reaching and invading host cells. I demonstrate that mucin and mucin glycans block S. Typhimurium’s ability to infect host epithelial cells. I further reveal that mucin and mucin glycans prevent infection by signaling to strongly downregulate multiple virulence genes in S. Typhimurium, including Salmonella pathogenicity island 1 (SPI-1), which is required for host cell invasion. Together, my results elucidate new ways in which mucin modulates pathogen behavior and opens the possibility to future mucin-based therapeutics. |
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