Super gene MUC5B provides mucus required for strong airway defense

In a typical day, each of us swallows 30 milliliters of mucus from our lungs. A mucus blanket is swept from the most distant airways up the trachea and swallowed all day long.

At the same time, we breathe 10,000 liters of air that is full of microorganisms -- bacteria, fungi, and viruses. The microorganisms deposited in our lungs land on the mucus and stick to it. Normally the mucus is moved out of the lungs by efficient action of hair-like structures called cilia. But when it isn't, the body is susceptible to respiratory infections in numerous respiratory diseases.

Researchers in a multi-center, international study that originated at MD Anderson have determined the major roles of two genes, MUC5AC and MUC5B, and how they affect mucus in the airways. The most recent results of the study, published in Nature, show that MUC5B is required for controlling airway infections, while MUC5AC is not.

The idea for the project was developed in the lab of Burton Dickey, M.D., professor and chair, Department of Pulmonary Medicine, when collaborating author Chris Evans, Ph.D., was a postdoctoral fellow in his lab. Now an associate professor at the University of Colorado, Evans and his colleagues completed the project. "Chris had studied airway biology before coming to MD Anderson, so I suggested we develop a project focused on mucus because there are many lung diseases, such as asthma, cystic fibrosis, COPD, and pulmonary fibrosis where mucus clearly plays a role," Dickey says.

Evans knocked the genes out of two sets of mice, beginning with the MUC5AC gene. The results of the MUC5AC mice study, published in an article in 2011 in Journal of Experimental Medicine, found that mice without MUC5AC were healthy and had normal life spans.

"Their only defect was they couldn't clear parasitic worms from the lungs and the gut. The major clue was that MUC5AC goes way up in allergic reactions like asthma, and allergic diseases resemble a parasitic infection," he explains.

Without MUC5AC, mucus doesn't prevent infection Evans then produced the MUC5B knockout mice, still in the Dickey lab. Their production proved to be challenging, because mucins are the biggest proteins in the body, and their genes also are large. The knockout mice ultimately were developed, and died within 16 weeks of birth.

So why would the mice die?

"They died from bacterial infections," Dickey says. "Day in and day out, MUC5B is the mucin that forms airway mucus and carries all the bacteria and fungi out of the lungs. Take it away, and bacteria are going to infect your lungs and spread into your blood stream and kill you."

Researchers hope to use the results to develop targeted therapies to control mucin secretion. Ideally, the goal is to turn down MUC5AC and turn up MUC5B, Dickey says.

Co-authors Seyed Moghaddam, M.D., and Evans are studying the role of the airway mucus barrier in reducing exposure of the lung epithelium, or lining, to cigarette smoke and microbes that drive lung carcinogenesis.

Other MD Anderson co-authors on the study were lead author Michelle Roy, Melissa McElwee, Scott Evans, M.D., Samantha Alexander, Lindsey Bellinghausen, Alfred Song, Youlia Petrove, Michael Tuvim, Ph.D., Roberto Adachi, M.D., Maria De La Garza, M.D.,and Seyed Moghaddam, M.D. . From The University of Texas Health Science Center at Houston: Harry Karmouty-Quintana, Ph.D., Michael Blackburn, Ph.D., and Scott Drouin, Ph.D., of University of Texas Health Science Center Houston.