Dissecting the inner workings of mucus barrier could yield better drugs, prevent disease
Call it slime, call it snot, or just call it mucus – this slippery substance serves vital functions in our bodies. Cystic fibrosis, premature child birth and dry eye are all linked to unhealthy changes in the bodily mucus that limits bad germs and lubricates the lungs, eyes and other organs.
Katharina Ribbeck, the Eugene Bell Career Development Professor of Tissue Engineering at MIT, is leading an effort to understand how mucus works and to develop substitutes for when natural mucus production fails.
Katharina Ribbeck, the Eugene Bell Career Development Professor of Tissue Engineering at MIT, diagrams the molecular structure of mucin, which has a protein backbone and a brush-like array of attached sugars, or glycans. Photo: Denise MacPhail
Her research could help engineer new molecular structures that could prevent the passage of harmful germs while promoting drug absorption. It could also lead to a molecular diagnostic test for increased risk of premature birth.
Saliva, tear fluids and internal mucus that have wetting, lubricating and germ-blocking properties. The average person produces about a gallon of mucus each day, and it covers a very large surface area of wet cells in the body. "Your mouth and nose contain very delicate cells that have to be embedded in water all the time," Ribbeck says. When mucus dries out, the cells they protect don't work as well." Healthy mucus is remarkable for its ability to absorb large amounts of water.
Ribbeck is working to change the common perception of mucus, demonstrating that it not merely an "icky" waste product but a fascinating material with many important functions for health. (See related video.)
Mucus depends on mucins, biopolymers with a protein backbone and attached forest of sugar molecules. Tear fluid, for example, contains proteins, salt and mucins. The mucins provide the lubrication that lets the eyelid slide smoothly. Chronic dry eye results from a lack of mucins, and current remedies are less than ideal. "Artificial tear fluids contain the salt, but they lack the mucins, or mucin-like polymers. There are many others – artificial saliva, for example."
Keeping microbes in check
For a long time, Ribbeck says, mucus was thought to function mostly as a structural barrier to germs. But her lab's research has shown that mucus does much more. "The picture is emerging that mucus is very good at preventing virulence of certain microbes," Ribbeck says. "Mucus has the ability to keep microbes in check – to keep them in a commensal, compatible way, so that they live on us but don't cause harm.
"This is different from the way antibiotics work. Antibiotics kill bacteria. Mucus doesn't kill them, but it prevents them from doing bad things, for example, colonizing your epithelial surfaces, wet surfaces, and expressing certain virulence factors," Ribbeck said. Mucus can also keep yeast such as Candida albicans from making the transition to a hyphal form with long filaments that can damage the epithelia. "Yeast cells in mucins remain in the benign form, which the body presumably can tolerate," she says. "We think mucin prevents their virulence."
"We are asking how microbes change their behavior when they get exposed to the mucins," Ribbeck says. "Bit by bit, with genetic perturbations of the microbes, and biochemical dissection of the mucins, we can begin to understand the mechanisms of interaction between the mucins and the microbes."
Mucins have also evolved strategies to prevent viral infections. "We're just beginning to understand how they do that," Ribbeck says. "But it looks like they can act against a broad range of different viruses that are experts in infecting mucosal epithelia. HIV, influenza, papilloma virus, herpes virus – all need to pass through mucus to achieve infection, and usually your mucus is really good at preventing them from passing through. We're dissecting the mechanisms now by which the mucins do that, to then build synthetic molecules that can do the same job."
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Predicting preterm birth risk
Another place mucus operates is in the cervix. During pregnancy, a dense plug of mucus in the cervical canal prevents germs from entering the uterus and harming the developing fetus. Uterine infection is a well-documented cause of premature birth. A diagnostic test to determine risk of premature birth could reduce health-care costs and improve care for mothers and babies. At least one of every 10 babies born worldwide is born prematurely, and premature births add $26 billion to the U.S. health-care price tag every year, according to a 2006 report.
In collaboration with Dr. Michael House, assistant professor of maternal-fetal medicine at Tufts University School of Medicine, Ribbeck's lab is studying cervical mucus with the aim of developing a simple molecular test that could determine risk for preterm birth. In general, the lab is looking for molecular fingerprints for healthy and diseased mucus across the different surfaces of the body. It's still a relatively young field, said Ribbeck, who started the work at Harvard in 2007.
Controlling ionic charge
Leon Li , a post-doctoral associate in Ribbeck's group, demonstrated that ionic charges on molecules and the spatial arrangement of those charges each play a key role in transport through mucus. (See related story.) Li tested positively charged peptides, negatively charged peptides and peptides carrying a mix of negative and positive charges in two different arrangements to show that that spatial arrangements of ionic charge can affect transport.
The new findings point to a new tool for designing drug and gene carriers – specific surface charge configurations to optimize interactions with mucins in mucus for diseases such as cystic fibrosis and gastric ulcers.
Recovering water-absorbing capacity
In collaboration with Johnson and Johnson, MIT post-doctoral associate Thomas Crouzier showed that removing sugars from pig gastric mucin (PGM) weakens its lubricating and water-absorbing capacities. But Crouzier's research showed that substituting a lectin-polyethylene glycol compound for the sugar in partially stripped PGM almost completely restored its water-absorbing capacity, and partially restored its lubricating capacity. The research team's paper is still in process. (See related story.)
"Now we know where to begin," Ribbeck says. "Deciphering the contribution of the mucin-associated glycans, also for lubrication, and then, importantly, developing a simple strategy for recovery, is exciting. This is a first step in the direction of creating synthetic mucins, and we're following up on that in different ways," Ribbeck said.
Written by Denis Paiste, Materials Processing Center.