MIT researchers identify components of mucus that can prevent fungal infections

Candida albicans It is a yeast that mostly lives in the human digestive system and mouth, as well as in the urinary and reproductive organs. Usually, it does not cause disease in its host, but under certain conditions, it can turn into a harmful form. Most candida Infections are not fatal, but systemic candida The infection, which affects the blood, heart, and other parts of the body, can be life-threatening.

MIT researchers have now identified the components of mucus it can interact with Candida albicans and prevent it from causing infection. These molecules, known as glycans, are a major component of myosin, the gel-forming polymers that make up mucus.

Myosin contains many different glycans, which are complex sugar molecules. A growing body of research indicates that glycans can be customized to help tame specific pathogens–; Not only Candida albicans But also other pathogens such as Pseudomonas aeruginosa And the Staphylococcus aureussays Katharina Rebek, Andrew and Irna Viterby Professor at MIT.

“The picture that emerges is that mucus displays an extensive small-molecule library with lots of virulence inhibitors against all kinds of problem pathogens, ready to be discovered and utilized,” says Rebek, who led the research group.

Taking advantage of these myosins could help researchers design 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.

Also among the key members of the research team are Rachel Heffy, Research Associate at the University of Basel; Michel Temayer, Professor of Biochemistry and Molecular Biology at the University of Georgia; Richard Cummings, professor of surgery at Harvard Medical School; Clarissa Noble, Associate Professor of Molecular and Cell Biology at the University of California, Merced; and Daniel Wozniak, professor of microbial infection, immunity, and microbiology at The Ohio State University.

Julie Takagi, a graduate student at the Massachusetts Institute of Technology, is the lead author of the paper that appears today in chemical nature biology.

The fungi are among us

Over the past decade, Rebek and others have discovered that mucus, far from being an inert waste product, plays an active role in controlling potentially harmful microbes. Within the mucus that lines most of the body are densely packed communities of different microbes, many of which are beneficial but some are harmful.

Candida albicans It is among the microbes that can be harmful if not contained, causing infections in the mouth and throat known as thrush, or vaginal yeast infections. These infections can usually be cleared up with antifungal, but invasive medications Candida albicans Infections of the bloodstream or internal organs, which can occur in people with weakened immune systems, have a mortality rate of up to 40 percent.

Ribbeck’s previous work showed that mucins can prevent Candida albicans The cells have to switch from a round yeast shape into multicellular filaments called hyphae, which are the harmful version of the microbe. Hyphae can secrete toxins that damage the immune system and essential tissues, and are also necessary for the formation of biofilms, a hallmark of infection.

Most candida The infection is caused by pathogenic biofilms, which are intrinsically resistant to the host’s immune system and antifungal treatments, posing significant clinical challenges to treatment.”

Julie Takagi, a graduate student at MIT, lead author of the paper

In the mucus, yeast cells continue to grow and thrive, but they do not become pathogenic.

“These pathogens do not appear to cause harm to healthy individuals,” Rebek says. “Something in mucus has evolved over millions of years, and it seems to keep pathogens in check.”

Mucins consist 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 explore whether glycans could be disarmed Candida albicans On their own, separate from the myosin backbone, or if the entire myosin molecule is essential.

After separating the glycans from the backbone, the researchers exposed them to them Candida albicans And found that these groups of glycans can inhibit monocytes candida from the formation of bristles. They can also suppress adhesion and biofilm formation, changing the dynamics Candida albicans Interaction with other microbes. This was true for the mucin glycans that came from human saliva and animal stomach and intestinal mucus.

It is very difficult to isolate single glycans from these groups, so Heavi’s team at the University of Basel synthesized six different glycans that are abundantly abundant on mucosal surfaces, and used them to test whether single glycans could disarm. Candida albicans.

“It is nearly impossible to isolate individual glycans from mucus samples using current techniques,” Heffy says. “The only way to study the properties of individual glycans is to synthesize them, which involves very complex and lengthy chemical procedures.” She and her colleagues are among a small number of research groups around the world who are developing ways to synthesize these complex molecules.

Tests at Ribbeck’s lab found that each of these glycans showed at least some ability to turn off the wick on their own, and some were as powerful as the combinations of multiple glycans the researchers tested earlier.

analysis candida Gene expression identified over 500 genes that were either down-regulated or down-regulated following interactions with glycans. These included not only genes involved in filament and biofilm formation but also 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, which is a key regulator activated by glycans.

“It appears that the glycans really take advantage of the physiological pathways and rewire those microbes,” Rebek says. “It’s a huge arsenal of molecules that enhance host compatibility.”

The analyzes performed in this study also allowed the researchers to link specific samples of myosin to the glycan structures within them, allowing them to further explore how those structures relate to microbial behaviors, Temayer says.

“Using state-of-the-art glycomic methods, we are beginning to comprehensively quantify the richness of myosinglycan diversity and explain this diversity into forms that have functional implications for both the host and the microbe,” he says.

molecular library

This study, along with Ribbeck’s previous work on pseudo aeruginosa and ongoing studies Staphylococcus aureus And the cholera vibrioindicates that different glycans specialize in inactivating different types of microbes.

She hopes that by harnessing this diverse group of glycans, researchers will be able to develop new treatments that target different infectious diseases. As an example, glycans can be used to either stop a file candida infection or help sensitize it to existing antifungal drugs, by breaking up the strands that form it in the pathogenic state.

“Glycans alone can reverse infection and transformation.” candida to a less harmful growth condition for the body, says Rebek. “They may also sensitize microbes to antifungals, because they make them individual, and therefore also make them more controllable by immune cells.”

Ribbeck is now working with drug delivery collaborators to find ways to deliver mucin glycans inside the body or on surfaces such as the skin. It also has several ongoing studies on how glycans affect a variety of different microbes. “We’re moving through different pathogens, and learning how to take advantage of this amazing set of natural regulatory molecules,” she says.

“I’m really excited about this new work because I think it has important implications for how we develop new antimicrobial therapies in the future,” says Nobile. “If we figure out how to deliver or therapeutically increase these protective mucin glycans into the human mucosal layer, we could potentially prevent and treat infection in humans by maintaining the microorganisms in their commensal forms.”

The research was funded by the National Institutes of Health, the National Science Foundation, the US Army Research Office through the Institute for Collaborative Biotechnology, and the Swiss National Science Foundation.

source:

Journal reference:

Takagi, c. et al. (2022) Mucin O-glycans are natural inhibitors of Candida albicans pathogenesis. chemical nature biology. doi.org/10.1038/s41589-022-01035-1.

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