Mucins are huge gel-forming polymers found inside the mucus barrier that prevent Candida albicans from switching from yeast to hyphae, a significant virulence function for this important human fungal disease. Despite their potential for therapeutic intervention, the molecular patterns in mucins that prevent filamentation are unknown.
MIT Researchers have now discovered mucus components that interact with Candida albicans and inhibit infection. These molecules, known as glycans, are a significant component of mucins, the gel-forming polymers that make up mucus.
Mucins consist of several glycans, complex sugar molecules. According to research, glycans can be specialized to help tame specific pathogens such as Candida albicans, Pseudomonas aeruginosa and Staphylococcus aureus.
Katharina Ribbeck, Professor Andrew and Erna Viterbi at MIT, said: “The emerging picture is that mucus shows an extensive library of small molecules with lots of virulence inhibitors against all sorts of problematic pathogens, ready to be detected and exploited.”
Using these mucins can help researchers develop new antifungal treatments or make pathogenic fungi more vulnerable to existing drugs. There are few such medicines on the market right now, and some harmful fungi have gained resistance.
The previous study suggested that mucins could prevent Candida albicans cells from switching from their round yeast form to multicellular filaments called hyphae, which are the harmful version of the microbe. Hyphae can secrete toxins that damage the immune system and the underlying tissue and are essential for biofilm formation, a hallmark of infection.
MIT doctoral student Julie Takagi, the paper’s lead author, said: “Most Candida infections are caused by pathogenic biofilms, which are inherently resistant to host immune system and antifungal therapies, which pose significant clinical challenges for treatment. “
Mucus in yeast cells continues to grow and thrive but does not become pathogenic. There must be something in the mucus that has evolved over millions of years to keep pathogens in check.
In this study, researchers wanted to determine if glycans could disarm Candida albicans on their own, decoupled from the mucin’s backbone, or if the entire mucin molecule is necessary.
For their study, researchers 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 can also inhibit adhesion and biofilm development and alter the dynamics of Candida Albican’s interactions with other microorganisms. Mucin giants from human saliva and animals’ gastrointestinal mucus were similar.
It is difficult to isolate single glycans, so researchers synthesized six different glycans that occur most on mucosal surfaces. They used them to test whether individual glycans could disarm Candida albicans.
Rachel Hevey, a research assistant at the University of Basel, said: “Individual glycans are almost impossible to isolate from mucus samples with current technologies. The only way to study the properties of individual glycans is to synthesize them, which involves extremely complicated and lengthy chemical procedures.”
After testing, they found that each of these glycans showed at least some ability to stop filamentation independently. Some were as potent as the collections of several glycans that the researchers had previously tested.
According to a study on Candida gene expression, more than 500 genes are up- or down-regulated in response to interactions with glycans. These genes included 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 triggered by glycans.
Ribbeck says, “Glycans appear to utilize physiological pathways and switch these microbes. There is 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 enabled the researchers to link specific mucin samples to the glycan structures present within them, which should enable them to further explore how these structures correlate with microbial behavior.”
“Using state-of-the-art glycomic methods, we have begun to define the richness of mucinglycan diversity in a comprehensive way and to comment on that diversity in motifs that have functional implications for both the host and the microbe.”
By utilizing the different glycans, researchers can one day develop new treatments for various infectious diseases. As an example, glycans can be used to either stop a Candida infection or help sensitize it to existing antifungal drugs by breaking up the filaments they form in the pathogenic state.
Ribbeck says, “Glycans alone can potentially reverse an infection and turn Candida into a growth condition that is less harmful to the body. They can also sensitize the microbes to fungicides 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 the pathogenicity of Candida albicans. Nat Chem Biol (2022). DOI: 10.1038 / s41589-022-01035-1
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