candida albicans is a yeast that often lives in the human digestive tract and mouth, as well as urinary and reproductive organs. Usually it does not cause disease in its host, but under certain circumstances it can switch to a harmful form. Most candida infections are not fatal, but systemic candida infection, which affects the blood, heart, and other parts of the body, can be life-threatening.
MIT researchers have now identified components of mucus that may interact with candida albicans and prevent it from causing an infection. These molecules, known as glycans, are a major component of mucins, the gel-forming polymers that make up mucus.
Mucins contain many different glycans, which are complex sugar molecules. A growing body of research suggests that glycans may be specialized to tame specific pathogens -; not only candida albicans but also other pathogens such as Pseudomonas aeruginosa and Staphylococcus aureussays Katharina Ribbeck, the Andrew and Erna Viterbi Professor at MIT.
“The picture that emerges is that mucus exhibits an extensive small molecule library with many virulence inhibitors against all sorts of problematic pathogens, ready to be discovered and exploited,” said Ribbeck, who led the research group.
Using these mucins, researchers can develop new antifungal drugs or make disease-causing fungi more susceptible to existing drugs. Currently, there are few such drugs, and some types of pathogenic fungi have developed resistance to them.
Key members of the research team also include Rachel Hevey, a research associate at the University of Basel; Micheal Tiemeyer, professor of biochemistry and molecular biology at the University of Georgia; Richard Cummings, professor of surgery at Harvard Medical School; Clarissa Nobile, associate professor of molecular and cell biology at the University of California at Merced; and Daniel Wozniak, professor of microbial infection and immunity, and microbiology, at Ohio State University.
MIT graduate student Julie Takagi is the lead author of the article, which appears today in Nature Chemical Biology†
Mold among us
Over the past decade, Ribbeck and others have found that far from being an inert waste product, mucus plays an active role in keeping potentially harmful microbes in check. Within the mucus that lines much of the body are densely packed communities of various microbes, many beneficial but some harmful.
candida albicans is one of the microbes that can be harmful if not contained and cause infections of the mouth and throat known as thrush or vaginal yeast infections. These infections can usually be treated with antifungal medicines, but are invasive candida albicans Infections of the bloodstream or internal organs, which can occur in people with weakened immune systems, have a fatality rate of up to 40 percent.
Ribbeck’s previous work has shown that mucins can prevent: candida albicans cells switch from its 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 also essential for the formation of biofilms, a hallmark of infection.
Most candida Infections result from pathogenic biofilms, which are intrinsically resistant to the host’s immune system and antifungal agents, posing a major clinical challenge to treatment.”
Julie Takagi, MIT graduate student, lead author of the paper
In mucus, yeast cells continue to grow and thrive, but they do not become pathogenic.
“These pathogens do not appear to cause harm in healthy individuals,” Ribbeck says. “There’s something in mucus that has evolved over millions of years that seems to keep pathogens in check.”
Mucins are made up of hundreds of glycans attached to a long protein backbone to form a bottle brush-like structure. In this study, Ribbeck and her students wanted to investigate whether glycans can disarm candida albicans on its own, separate from the mucin backbone, or if the whole mucin molecule is needed.
After the glycans separated from the spine, the researchers exposed them to: candida albicans and found that these collections of glycans can prevent unicellular candida of forming filaments. They can also suppress adhesion and biofilm formation and improve the dynamics of candida albicans interaction with other microbes. This was true for mucin glycans derived from human saliva and animal stomach and intestinal mucus.
It is very difficult to isolate individual glycans from these collections, so the Hevey researchers at the University of Basel synthesized six different glycans most commonly found on mucosal surfaces, and used them to test whether individual glycans can disarm. candida albicans†
“Individual glycans are nearly impossible to isolate from mucus samples with current technologies,” Hevey says. “The only way to study the characteristics of individual glycans is to synthesize them, which involves extremely complicated and lengthy chemical procedures.” She and her colleagues are among a small number of research groups around the world that are developing methods to synthesize these complex molecules.
Tests in Ribbeck’s lab showed that each of these glycans showed at least some ability to stop filamentation on their own, and some were just as potent as the pools of multiple glycans the researchers had previously tested.
an analysis of candida gene expression identified over 500 genes that are either upregulated or downregulated after interactions with glycans. These include not only genes involved in filament and biofilm formation, but other roles such as amino acid synthesis and other metabolic functions. Many of these genes appear to be controlled by a transcription factor called NRG1, a master regulator that is activated by the glycans.
“The glycans really seem to tap into physiological pathways and rewire those microbes,” says Ribbeck. “It’s a huge arsenal of molecules that promote host compatibility.”
The analyzes performed in this study also allowed the researchers to link specific mucin samples to the glycan structures found in them, which should allow them to further investigate how those structures correlate with microbial behavior, Tiemeyer says.
“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,” he says.
A library of molecules
This study, combined with Ribbeck’s previous work on pseudomonas aeruginosa and ongoing studies of Staphylococcus aureus and Vibrio choleraesuggest that different glycans are specialized to incapacitate different types of microbes.
She hopes that by using this variety of glycans, researchers can develop new treatments that target various infectious diseases. As an example, glycans can be used to make either a candida infection or helping to sensitize to existing antifungal agents, by breaking down the filaments they form in the pathogenic state.
“Only the glycans can potentially reverse and convert an infection” candida to a growth state that is less harmful to the body,” Ribbeck says. “They can also sensitize the microbes to antifungals because they individualize them, which also makes them more manageable by immune cells.”
Ribbeck is now working with collaborators who specialize in drug delivery to find ways to release mucin glycans into the body or onto surfaces such as the skin. She also has several ongoing studies investigating how glycans affect different microbes. “We go through different pathogens and learn how to use this amazing array of natural regulatory molecules,” she says.
“I’m very excited about this new work because I think it has important implications for how we develop new antimicrobial therapies in the future,” said Nobile. “If we figure out how to therapeutically deliver or increase these protective mucin glycans in the human mucosal layer, we may be able to prevent and treat infections in humans by keeping microorganisms in their commensal form.”
The research was funded by the National Institutes of Health, the National Science Foundation, the US Army Research Office through the Institute for Collaborative Biotechnologies and the Swiss National Science Foundation.
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