Molecules in mucus may be the key to thwarting fungal infection

Thinking of mucus may disgust you. However, MIT researchers have now identified components of the substance that can interact with a particular yeast and prevent it from causing infection, according to a press release by the institution published this month.

Glycans to the rescue

These components are called glycans, and they are a major part of mucins, the gel-forming polymers that make up mucus. Research is now revealing that these glycans can be specialized to help fight many pathogens such as Candida albicans, Pseudomonas aeruginosa, and Staphylococcus aureus.

“The picture that is emerging is that mucus displays an extensive small-molecule library with lots of virulence inhibitors against all sorts of problematic pathogens, ready to be discovered and leveraged,” said in the statement Katharina Ribbeck, the Andrew and Erna Viterbi Professor at MIT who led the research group.

Now, researchers hope that these mucins could help researchers design new antifungal medicines or make disease-causing fungus more susceptible to existing drugs as some types of pathogenic fungus have developed resistance to them. However, spotting these glycans has been no easy task. 

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“Individual glycans are nearly impossible to isolate from mucus samples with current technologies,” said Rachel Hevey, a research associate at the University of Basel. “The only way to study the characteristics of individual glycans is to synthesize them, which involves extremely complicated and lengthy chemical procedures.”

Currently, only a small number of research groups worldwide are developing methods to synthesize these complex molecules, but the new study could inspire more research. The next step, of course, would be to find a way to deliver glycans to the human body.

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Drug delivery for mucus

Ribbeck is now working with collaborators who specialize in drug delivery to find such a solution. She also has underway many studies that explore how glycans affect a variety of different microbes. “We’re moving through different pathogens, learning how to leverage this amazing set of natural regulatory molecules,” she said. 

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“I am really excited about this new work because I think it has important implications for how we develop new antimicrobial therapies in the future,” Clarissa Nobile, an associate professor of molecular and cell biology at the University of California at Merced, said.

“If we figure out how to therapeutically deliver or increase these protective mucin glycans into the human mucosal layer, we could potentially prevent and treat infections in humans by maintaining microorganisms in their commensal forms.”

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What does this mean for now? Much more work needs to be done until mucus can actually fight infections but the studies are promising. In the meantime, the next time you sneeze or have a cold, you may want to remember that your mucus is actually protecting you.

The results of the study were published in the journal Nature Chemical Biology. 

Abstract:
Mucins are large gel-forming polymers inside the mucus barrier that inhibit the yeast-to-hyphal transition of Candida albicans, a key virulence trait of this important human fungal pathogen. However, the molecular motifs in mucins that inhibit filamentation remain unclear despite their potential for therapeutic interventions. Here, we determined that mucins display an abundance of virulence-attenuating molecules in the form of mucin O-glycans. We isolated and cataloged >100 mucin O-glycans from three major mucosal surfaces and established that they suppress filamentation and related phenotypes relevant to infection, including surface adhesion, biofilm formation and cross-kingdom competition between C. albicans and the bacterium Pseudomonas aeruginosa. Using synthetic O-glycans, we identified three structures (core 1, core 1 + fucose and core 2 + galactose) that are sufficient to inhibit filamentation with potency comparable to the complex O-glycan pool. Overall, this work identifies mucin O-glycans as host molecules with untapped therapeutic potential to manage fungal pathogens.

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