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How mucus tames microbes

More than 200 square meters of our bodies   including the digestive tract  lungs  and urinary tract   are lined with mucus. In recent years  scientists have found some evidence that mucus is not just a physical barrier that traps bacteria and viruses  but it can also disarm pathogens and prevent them from causing infections.

A new study from MIT reveals that glycans   branched sugar molecules found in mucus   are responsible for most of this microbe-taming. There are hundreds of different glycans in mucus  and the MIT team discovered that these molecules can prevent bacteria from communicating with each other and forming infectious biofilms  effectively rendering them harmless.

 What we have in mucus is a therapeutic gold mine   says Katharina Ribbeck  the Mark Hyman  Jr. Career Development Professor of Biological Engineering at MIT.  These glycans have biological functions that are very broad and sophisticated. They have the ability to regulate how microbes behave and really tune their identity.

In this study  which appears today in Nature Microbiology  the researchers focused on glycans  interactions with Pseudomonas aeruginosa  an opportunistic pathogen that can cause infections in cystic fibrosis patients and people with compromised immune systems. Work now underway in Ribbeck s lab has shown that glycans can regulate the behavior of other microbes as well.

The lead author of the Nature Microbiology paper is MIT graduate student Kelsey Wheeler.

Powerful defenders

The average person produces several liters of mucus every day  and until recently this mucus was thought to function primarily as a lubricant and a physical barrier. However  Ribbeck and others have shown that mucus can actually interfere with bacterial behavior  preventing microbes from attaching to surfaces and communicating with one another.

In the new study  Ribbeck wanted to test whether glycans were involved in mucus  ability to control the behavior of microbes. These sugar molecules  a type of oligosaccharide  attach to proteins called mucins  the gel-forming building blocks of mucus  to form a bottlebrush-like structure. Mucus-associated glycans have been little studied  but Ribbeck thought they might play a major role in the microbe-disarming activity she had previously seen from mucus.

To explore that possibility  she isolated glycans and exposed them to Pseudomonas aeruginosa. Upon exposure to mucin glycans  the bacteria underwent broad shifts in behavior that rendered them less harmful to the host. For example  they no longer produced toxins  attached to or killed host cells  or expressed genes essential for bacterial communication.

This microbe-disarming activity had powerful consequences on the ability of this bacterium to establish infections. Ribbeck has shown that treatment of Pseudomonas-infected burn wounds with mucins and mucin glycans reduces bacterial proliferation  indicating the therapeutic potential of these virulence-neutralizing agents.

 We ve seen that intact mucins have regulatory effects and can cause behavioral switches in a whole range of pathogens  but now we can pinpoint the molecular mechanism and the entities that are responsible for this  which are the glycans   Ribbeck says.

In these experiments  the researchers used collections of hundreds of glycans  but they now plan to study the effects of individual glycans  which may interact specifically with different pathways or different microbes.

Bacterial interactions

Pseudomonas aeruginosa is just one of many opportunistic pathogens that healthy mucus keeps in check. Ribbeck is now studying the role of glycans in regulating other pathogens  including Streptococcus and the fungus Candida albicans  and she is also working on identifying receptors on microbe cell surfaces that interact with glycans.

Her work on Streptococcus has shown that glycans can block horizontal gene transfer  a process that microbes often use to spread genes for drug resistance.

Ribbeck and other researchers are now interested in using what they have learned about mucins and glycans to develop artificial mucus  which could offer a new way to treat diseases stemming from lost or defective mucus.

Harnessing the powers of mucus could also lead to new ways to treat antibiotic-resistant infections  because it offers a complementary strategy to traditional antibiotics  Ribbeck says.

 What we find here is that nature has evolved the ability to disarm difficult microbes  instead of killing them. This would not only help limit selective pressure for developing resistance  because they are not under pressure to find ways to survive  but it should also help create and maintain a diverse microbiome   she says.

Ribbeck suspects that glycans in mucus also play a key role in determining the composition of the microbiome   the trillions of bacterial cells that live inside the human body. Many of these microbes are beneficial to their human hosts  and glycans may be providing them with nutrients they need  or otherwise helping them to flourish  she says. In this way  mucus-associated glycans are similar to the many oligosaccharides found in human milk  which also contains a wide array of sugars that can regulate microbe behavior.

 This is a theme that is likely at play in many systems where the goal is to shape and manipulate communities inside the body  not just in humans but throughout the animal kingdom   Ribbeck says.

The research was funded by the National Institute of Biomedical Imaging and Bioengineering  the National Institutes of Health  the National Science Foundation  the National Institute of Environmental Health Sciences  and the MIT Deshpande Center for Technological Innovation.