Mucins are huge ice-forming polymers found within the mucosal barrier that prevent Candida albicans from passing from yeast to hyphal, a major virulence feature of this important human fungal disease. Despite their potential for therapeutic intervention, the molecular patterns of mucins that hinder filamentation remain unknown.
MIT scientists have now discovered mucus components that interact with Candida albicans and inhibit infection. These molecules, known as glycans, are an important constituent of mucins, the ice-forming polymers that make up mucus.
Mucins consist of various glycans, complex molecules of sugar. According to research, glycans can specialize in helping to domesticate specific pathogens such as Candida albicans, Pseudomonas aeruginosa, and Staphylococcus aureus.
Katharina Ribbeck, MIT Professor Andrew and Erna Viterbi, said: “The emerging picture is that mucus shows a large library of small molecules with many virulence inhibitors against all sorts of problematic pathogens, ready to be discovered and exploited.” .
The use of these mucins could help scientists develop new antifungal treatments or make disease-causing fungi more vulnerable to existing drugs. There are few drugs on the market right now, and some harmful fungi have become resistant.
The previous study suggested that mucins can prevent Candida albicans cells from moving from their round yeast form to multicellular filaments called hyphae, which is the harmful version of the microbe. Hyphae can secrete toxins that damage the immune system and underlying tissue and are essential for the formation of biofilm, a hallmark of infection.
MIT graduate student Julie Takagi, the lead author of the article, said: “Most Candida infections result from pathogenic biofilms, which are intrinsically resistant to the host’s immune system and antifungal therapies. , which poses a significant clinical challenge for treatment. “
The mucus inside the 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 under control.
In this study, the scientists wanted to determine if glycans could disarm Candida albicans on their own, separate from the mucin spine, or if the entire mucin molecule is needed.
For their study, the scientists isolated the 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 the adhesion and development of the biofilm and change the dynamics of Candida Albicans interactions with other microorganisms. The mucin glycans of human saliva and animal gastric and intestinal mucus were similar.
Isolating single glucans is difficult, so scientists synthesized six different glycans that are more abundant on mucosal surfaces. They used them to test whether individual glycans can disarm Candida albicans.
Rachel Hevey, an associate researcher at the University of Basel, said: “It is almost impossible to isolate individual glycans from mucus samples with current technologies. The only way to study the characteristics 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 multiple glycan collections the researchers had previously tested.
According to a study on gene expression in Candida, more than 500 genes are regulated up or down 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 activated by glycans.
Ribbeck says, “Glycans appear to take advantage of physiological pathways and reconnect these microbes. It’s a huge arsenal of molecules that promote host compatibility.”
Micheal Tiemeyer, a professor of biochemistry and molecular biology at the University of Georgia, said: “The analysis in this study also allowed researchers to link specific mucin samples to existing glycan structures, which should to explore further how these structures are correlated with microbial behavior “.
“Using state-of-the-art glycomic methods, we have begun to define the richness of mucin glycan diversity in a comprehensive way and to record this diversity in motifs that have functional implications for both host and microbe.”
Taking advantage of the variety of glycans, scientists could one day develop new treatments for different infectious diseases. As an example, glycans could be used to stop a Candida infection or help sensitize it to existing antifungal drugs by breaking down the filaments they form in a pathogenic state.
Ribbeck says, “Glycans can only reverse an infection and turn Candida into a growth state that is less harmful to the body. They could also sensitize microbes to antifungals because they individualize them, making them more manageable for immune cells.” .
Magazine reference:
- 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