Candida albicans is among the microbes that can be harmful if not contained. Infections can usually be treated with antifungal drugs. However, invasive C. albicans infections of the bloodstream or internal organs have a fatality rate of up to 40%. Now, researchers from MIT report they have discovered that components of mucus, called glycans, interact with C. albicans and prevent it from causing infection. Their findings could pave the way for new antifungal medicines or help improve existing drugs against disease-causing fungus.
Their findings are published in the journal Nature Chemical Biology in a paper titled, “Mucin O-glycans are natural inhibitors of Candida albicans pathogenicity.”
“The picture that is emerging is that mucus displays an extensive small-molecule library with lots of virulence inhibitors against all sorts of problematic pathogens, ready to be discovered and leveraged,” said Katharina Ribbeck, the Andrew and Erna Viterbi professor at MIT.
Previous work by Ribbeck has demonstrated that mucins can prevent C. albicans cells from switching from its round yeast form to multicellular filaments called hyphae, which is the harmful version of the microbe.
“Most Candida infections result from pathogenic biofilms, which are intrinsically resistant to the host immune system and antifungal therapeutics, posing significant clinical challenges for treatment,” Julie Takagi, a PhD student in Ribbeck’s lab, said.
In mucus, yeast cells continue to grow and thrive, but they do not become pathogenic.
“These pathogens don’t seem to cause harm in healthy individuals,” Ribbeck said. “There is something in mucus that has evolved over millions of years, that seems to keep pathogens in check.”
Mucins consists of hundreds of glycans attached to a long protein backbone to form a bottlebrush-like structure. In this study, Ribbeck and her students wanted to explore whether glycans could disarm C. albicans on their own, detached from the mucin backbone, or if the entire mucin molecule is necessary.
After separating glycans from the backbone, the researchers exposed them to C. albicans and found that these collections of glycans could prevent single-celled Candida from forming filaments. They could also suppress adhesion and biofilm formation, and alter the dynamics of C. albicans interaction with other microbes. This was true for mucin glycans that came from human saliva and animal gastric and intestinal mucus.
“Individual glycans are nearly impossible to isolate from mucus samples with current technologies,” Rachel Hevey, PhD, research associate, University of Basel, said. “The only way to study the characteristics of individual glycans is to synthesize them, which involves extremely complicated and lengthy chemical procedures.”
Testing done in Ribbeck’s lab found that each of these glycans showed at least some ability to stop filamentation on their own.
“The glycans seem to really tap into physiological pathways and rewire those microbes,” Ribbeck said. “It’s a huge arsenal of molecules that promote host compatibility.”
“The glycans alone can potentially reverse an infection, and convert Candida to a growth state that is less harmful to the body,” Ribbeck said. “They also might sensitize the microbes to antifungals, because they individualize them, thereby also making them more manageable by immune cells.”
The researchers are currently seeking ways to deliver mucin glycans inside the body or on surfaces such as the skin. The team also has several studies underway investigating how glycans affect a variety of different microbes. “We’re moving through different pathogens, learning how to leverage this amazing set of natural regulatory molecules,” Ribbeck added.
