Mucins are huge gel-forming polymers found in the mucous barrier that prevent Candida albicans from transitioning from yeast to hyphal, a significant virulence characteristic of this important human fungal disease. Despite their potential for therapeutic intervention, the molecular patterns in mucins that impede filamentation remain unknown.
MIT scientists have now discovered mucus components that interact with Candida albicans and inhibit infection. These molecules, known as glycans, are a major component of mucins, the gel-forming polymers that make up mucus.
Mucins are made up of several glycans, complex sugar molecules. According to research, glycans can be specialized in taming specific pathogens such as Candida albicans, Pseudomonas aeruginosa and Staphylococcus aureus.
Katharina Ribbeck, the Andrew and Erna Viterbi Professor at MIT, said: “The emerging picture is that mucus exhibits an extensive library of small molecules with many virulence inhibitors against a variety of problematic pathogens, ready to be discovered and used.”
Using these mucins could help scientists develop new antifungal treatments or make disease-causing fungi more vulnerable to existing drugs. There are currently few such drugs on the market and some harmful fungi have acquired resistance.
The previous study suggested that mucins may prevent Candida albicans cells from switching from their round yeast shape to multicellular filaments called hyphae, the harmful version of the microbe. Hyphae can secrete toxins that damage the immune system and underlying tissue and are essential for biofilm formation, a hallmark of infection.
MIT graduate student Julie Takagi, the paper’s lead author, said: “Most Candida infections result from pathogenic biofilms, which are intrinsically resistant to the host immune system and antifungal therapies, which pose significant clinical challenges to treatment.”
Mucus in yeast cells continues to grow and thrive, but does not become pathogenic. There must be something in mucus that has evolved over millions of years to control pathogens.
In this study, scientists wanted to determine whether glycans can disarm Candida albicans alone, separate from the mucin backbone, or whether the entire mucin molecule is required.
For their research, scientists isolated glycans from the spine and exposed them to Candida albicans. They found that these collections of glycans could prevent unicellular Candida from forming filaments. They may also inhibit the adhesion and development of biofilms and alter the dynamics of Candida Albicans’ interactions with other microorganisms. Mucin glycans from human saliva and animal gastric and intestinal mucus were comparable.
Isolating single glycans is difficult, so scientists have synthesized six different glycans that are most abundant on mucosal surfaces. They used them to test whether individual glycans can disarm Candida albicans.
Rachel Hevey, a research associate at the University of Basel, said: “Individual glycans are almost impossible to isolate from slime samples with current technologies. The only way to study the properties of individual glycans is to synthesize them, which requires extremely complicated and lengthy chemical procedures.”
After testing, they found that each of these glycans showed at least some ability to independently stop filamentation. Some were as potent as the multiple glycan pools the researchers had previously tested.
According to a study on Candida gene expression, more than 500 genes are upregulated or downregulated in response to interactions with glycans. These genes include filament and biofilm formation genes and genes involved in amino acid synthesis and other metabolic processes. Many of these genes appear to be regulated by the transcription factor NRG1, a master regulator activated by glycans.
Ribbeck says, “The glycans seem to tap into physiological pathways and rewire those microbes. It’s a huge arsenal of molecules that promote host compatibility.”
Micheal Tiemeyer, professor of biochemistry and molecular biology at the University of Georgia, said: “The analyzes performed in this study also allowed the researchers to link specific mucin samples to the glycan structures found within them, which should allow them to further investigate how those structures correlated with microbial behavior.”
“Using state-of-the-art glycomic methods, we have begun to comprehensively define the richness of mucin-glycan diversity and annotate that diversity in motifs that have functional implications for both the host and the microbe.”
By exploiting the variety of glycans, scientists could one day develop new treatments that target various infectious diseases. As an example, glycans can be used to either stop a Candida infection or help sensitize existing antifungal agents by breaking the filaments they form in the pathogenic state.
Ribbeck say† “Only the glycans can potentially reverse an infection and convert Candida into a growth state that is less harmful to the body. They can also sensitize the microbes to antifungals because they individualize them, making them more manageable by immune cells.”
- Takagi, J., Aoki, K., Turner, BS, et al. Mucin O-glycans are natural inhibitors of Candida albicans pathogenicity. Nat Chem Biol (2022). DOI: 10.1038/s41589-022-01035-1
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