Fighting Fungal Infections with Mucus

Fighting Fungal Infections with Mucus

Scientists may have identified a new molecule that can help combat fungal infections, and it has to do with mucus

Nobody wants a fungal infection – and if you happen to get one, you want it to be dealt with immediately. A current concern in fighting these types of infections is that fungi can become resistant to one of the three types of available antifungal drugs. Some fungal pathogens can even become resistant to all three types. That is why scientists are always hunting for new therapeutics, and recently, may have identified a new molecule to combat fungal infections that avoids antifungal resistance. Interestingly, this molecule comes from our mucus.

Mucus is a complex secretion that acts as a protective layer by coating many surfaces inside the body that are exposed to the outside world (e.g. nose and colon). Mucus is made up of mostly water and several other compounds, like mucins (a relatively enormous, sugary protein), that give it a sticky, gelatinous texture. Previous studies, like one conducted in 2014, found that mucins in mucus reduce the ability of fungal pathogens to cause infections. Now, a study by a group of scientists recently published in the journal Nature Chemical Biology identified specific parts of the mucin protein that are responsible for inhibiting the fungal pathogen.

In this study, the scientists tested for antifungal effects on a model fungal pathogen, Candida albicans, which is a very common pathogen that infects humans. C. albicans  is a single celled budding yeast and typically lives inside us commensally (or without causing any harm). When someone becomes immunocompromised, or if a person’s microbiome gets disrupted (such as when taking antibiotics) then C. albicans can grow out of control and cause common yeast infections (called candidiasis). These infections include oral thrush or vaginal candidiasis, and more serious and possibly fatal infections called invasive candidiasis.

Image of Candida albicans growing on an agar plate. Image by Matthew Vandermeulen, PhD.

For the beginning of the study, the scientists verified previous findings by mixing C. albicans with mucus (from pig intestines/stomach, and human saliva) and confirming mucus prevents pathogenic behaviors (behaviors required to cause infection). The scientists then tested if the effect by mucus was more specifically due to the mucin proteins it contains by filtering out the mucins and re-testing. They found that removing mucins decreased the effectiveness of mucus on pathogenic behaviors and adding mucins back restored it. They also used a molecular technique and found that mucins turn off genes in C. albicans that are required for them to cause infection. So overall, the scientists were able to confirm that mucins are a major part in mucus that prevents pathogenic behaviors.

But what part of the mucin protein is important for its antifungal effects? This is a critical question because narrowing in on a precise molecular mechanism increases the chance of establishing a molecule as a potential therapeutic. Therefore, the scientists dug deeper.

… This is a critical question because narrowing in on a precise molecular mechanism increases the chance of establishing a molecule as a potential therapeutic…

Mucin proteins have chains of sugars attached to them that form branching structures referred to as glycans. The scientists wanted to test if these glycans were responsible for the ability of mucins to prevent pathogenic behaviors. Using a biochemical technique, the researchers isolated the branching glycan chains from mucin proteins (>100 different types). They then mixed this pool of different glycans with C. albicans and found that the glycans were able to shut off genes required for pathogenic behaviors – similarly to whole mucins. One pathogenic behavior of fungal cells is the ability to adhere to a surface. The researchers showed that glycans, and not other sugar molecules, prevent surface adherence. So the scientists have found the specific part of the mucin that is preventing pathogenic behaviors – the glycans.

Figure 1A of Takagi et al., Nature Chemical Biology, 2022. Model of C. albicans interacting with a mucin protein in mucus. Glycan structures are represented as different colored shapes on the right side.

But out of the different types of glycans, are there specific ones that are better than others at preventing pathogenic behaviors? To address this question, the scientists synthesized the six most abundantly found glycans isolated in this study and tested them. They identified that three of these glycans were able to prevent pathogenic behaviors similarly to the entire glycan pool. This suggests that these three glycan structures may be the key.

The findings from this study could have important ramifications for the world of medicine. With new fungal pathogens emerging, like Candida auris, that can become resistant to multiple or all antifungal drugs, it is imperative to have diverse options to treat infections. Additionally, mucin glycans come with a unique feature; they likely will not trigger antifungal resistance. This is because glycans don’t actually kill the fungus; they just prevent fungal cells from behaving pathogenetically and allow the immune system to maintain them in their commensal state. Because fungal cells aren’t killed, resistance to the glycans has a low likelihood of evolving.

…Because fungal cells aren’t killed, resistance to the glycans has a low likelihood of evolving…

Much research will still have to be done before mucin glycans can be used as a treatment though. For example, glycans that are not attached to a larger molecule are generally ineffective as a pharmaceutical. Therefore, scientists will have to come up with a backbone molecule to attach these newly identified glycans to in order to produce an efficient therapeutic.

Additionally, scientists will have to test the effectiveness of these glycans’ in a real setting. In the study explained above, the researchers performed an experiment to test the effectiveness of whole mucins on fungal infections in mice. The results implied mucins aid the immune system in suppressing fungal infections, but to be honest, the effect seemed a little weak. Perhaps in a future study scientists will get better results if, instead of using whole mucins, they synthesize a molecule that contains only the three newly identified glycan structures.

There is still plenty to learn about fungal pathogens as well. For example, even though scientists identified specific glycans that prevent pathogenic behaviors, it is still unknown how glycans actually interact with fungal cells. What proteins on the surface of a fungal cell do glycans bind to? How do glycans actually trigger the molecular decision of a fungus to not behave pathogenetically? Do glycans actually enter the fungal cell or just bind to the surface? These are important questions to answer in future work.

…All and all, this study has made a major advance in our understanding of mucin biology that could lead to new antifungal therapeutics…

All and all, this study has made a major advance in our understanding of mucin biology that could lead to new antifungal therapeutics. It is fascinating that a possible therapeutic may come ‘directly’ from our own body. It kind of makes you wonder, are there other anti-pathogen molecules in other body secretions just waiting to be found?

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