mucus – NIH Director's Blog (original) (raw)
Single-Cell Study Offers New Clue into Causes of Cystic Fibrosis
Posted on May 27th, 2021 by Dr. Francis Collins
Credit: Carraro G, Nature, 2021
More than 30 years ago, I co-led the Michigan-Toronto team that discovered that cystic fibrosis (CF) is caused by an inherited misspelling in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1]. The CFTR protein’s normal function on the surface of epithelial cells is to serve as a gated channel for chloride ions to pass in and out of the cell. But this function is lost in individuals for whom both copies of CFTR are misspelled. As a consequence, water and salt get out of balance, leading to the production of the thick mucus that leaves people with CF prone to life-threatening lung infections.
It took three decades, but that CFTR gene discovery has now led to the development of a precise triple drug therapy that activates the dysfunctional CFTR protein and provides major benefit to most children and adults with CF. But about 10 percent of individuals with CF have mutations that result in the production of virtually no CFTR protein, which means there is nothing for current triple therapy to correct or activate.
That’s why more basic research is needed to tease out other factors that contribute to CF and, if treatable, could help even more people control the condition and live longer lives with less chronic illness. A recent NIH-supported study, published in the journal Nature Medicine [2], offers an interesting basic clue, and it’s visible in the image above.
The healthy lung tissue (left) shows a well-defined and orderly layer of ciliated cells (green), which use hair-like extensions to clear away mucus and debris. Running closely alongside it is a layer of basal cells (outlined in red), which includes stem cells that are essential for repairing and regenerating upper airway tissue. (DNA indicating the position of cell is stained in blue).
In the CF-affected airways (right), those same cell types are present. However, compared to the healthy lung tissue, they appear to be in a state of disarray. Upon closer inspection, there’s something else that’s unusual if you look carefully: large numbers of a third, transitional cell subtype (outlined in red with green in the nucleus) that combines properties of both basal stem cells and ciliated cells, which is suggestive of cells in transition. The image below more clearly shows these cells (yellow arrows).
Credit: Carraro G, Nature, 2021
The increased number of cells with transitional characteristics suggests an unsuccessful attempt by the lungs to produce more cells capable of clearing the mucus buildup that occurs in airways of people with CF. The data offer an important foundation and reference for continued study.
These findings come from a team led by Kathrin Plath and Brigitte Gomperts, University of California, Los Angeles; John Mahoney, Cystic Fibrosis Foundation, Lexington, MA; and Barry Stripp, Cedars-Sinai, Los Angeles. Together with their lab members, they’re part of a larger research team assembled through the Cystic Fibrosis Foundation’s Epithelial Stem Cell Consortium, which seeks to learn how the disease changes the lung’s cellular makeup and use that new knowledge to make treatment advances.
In this study, researchers analyzed the lungs of 19 people with CF and another 19 individuals with no evidence of lung disease. Those with CF had donated their lungs for research in the process of receiving a lung transplant. Those with healthy lungs were organ donors who died of other causes.
The researchers analyzed, one by one, many thousands of cells from the airway and classified them into subtypes based on their distinctive RNA patterns. Those patterns indicate which genes are switched on or off in each cell, as well as the degree to which they are activated. Using a sophisticated computer-based approach to sift through and compare data, the team created a comprehensive catalog of cell types and subtypes present in healthy airways and in those affected by CF.
The new catalogs also revealed that the airways of people with CF had alterations in the types and proportions of basal cells. Those differences included a relative overabundance of cells that appeared to be transitioning from basal stem cells into the specialized ciliated cells, which are so essential for clearing mucus from the lungs.
We are not yet at our journey’s end when it comes to realizing the full dream of defeating CF. For the 10 percent of CF patients who don’t benefit from the triple-drug therapy, the continuing work to find other treatment strategies should be encouraging news. Keep daring to dream of breathing free. Through continued research, we can make the story of CF into history!
References:
[1] Identification of the cystic fibrosis gene: chromosome walking and jumping. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N, et al. Science.1989 Sep 8;245(4922):1059-65.
[2] Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition. Carraro G, Langerman J, Sabri S, Lorenzana Z, Purkayastha A, Zhang G, Konda B, Aros CJ, Calvert BA, Szymaniak A, Wilson E, Mulligan M, Bhatt P, Lu J, Vijayaraj P, Yao C, Shia DW, Lund AJ, Israely E, Rickabaugh TM, Ernst J, Mense M, Randell SH, Vladar EK, Ryan AL, Plath K, Mahoney JE, Stripp BR, Gomperts BN. Nat Med. 2021 May;27(5):806-814.
Links:
Cystic Fibrosis (National Heart, Lung, and Blood Institute/NIH)
Kathrin Plath (University of California, Los Angeles)
Brigitte Gomperts (UCLA)
Stripp Lab (Cedars-Sinai, Los Angeles)
Cystic Fibrosis Foundation (Lexington, MA)
Epithelial Stem Cell Consortium (Cystic Fibrosis Foundation, Lexington, MA)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; National Cancer Institute; National Center for Advancing Translational Sciences
Posted In: News
Tags: basal cells, cell biology, CF, CFTR, ciliated cells, cystic fibrosis, Cystic Fibrosis Foundation, epithelial cells, Epithelial Stem Cell Consortium, gene expression, lungs, mucus, rare disease, RNA, single cell analysis, single cell sequencing, transitional cell subtype, upper airway
A Close-up of COVID-19 in Lung Cells
Posted on December 17th, 2020 by Dr. Francis Collins
Credit: Ehre Lab, UNC School of Medicine
If you or a loved one have come down with SARS-CoV-2, the coronavirus responsible for COVID-19, you know it often takes hold in the respiratory system. This image offers a striking example of exactly what happens to cells in the human airway when this coronavirus infects them.
This colorized scanning electron microscope (SEM) image shows SARS-CoV-2-infected human lung cells (purple) covered in hair-like cilia (blue). Those cilia line the inner surface of the airways and help to clear mucus (yellow-green) containing dust and other debris from the lungs. Emerging from the surface of those infected airway cells are many thousands of coronavirus particles (red).
This dramatic image, published recently in the New England Journal of Medicine, comes from the lab of pediatric pulmonologist Camille Ehre, University of North Carolina at Chapel Hill. Ehre and team study mucus and how its properties change in cystic fibrosis, chronic obstructive pulmonary disease (COPD), and various other conditions that affect the lungs. These days, they’re also focusing their attention on SARS-CoV-2 and potentially new ways to block viral entry into cells of the human airway.
As part of that effort, she and her colleagues captured this snapshot of SARS-CoV-2 viruses exiting from lung cells in a lab dish. They first cultured cells from the lining of a human airway, then inoculated them with the virus. Ninety-six hours later, this is what they saw in greyscale. The vivid colors were added later by UNC medical student Cameron Morrison.
The image illustrates the astoundingly large number of viral particles that can be produced and released from infected human cells. Ehre notes that in a lab dish containing about a million human cells, they’ve witnessed the virus explode from about 1,000 particles to about 10 million in just a couple of days.
The dramatic increase in viral particles helps to explain how COVID-19 spreads so easily from the lungs to other parts of the body and—all too often—on to other individuals, especially in crowded, indoor places where people aren’t able to keep their distance. Hopefully, images like this one will help to inspire more of us this winter to avoid the crowds (especially indoors), wear masks, and wash our hands frequently.
Reference:
[1] SARS-CoV-2 infection of airway cells. Ehre C. NEJM. 2020 Sep 3;383(10):969.
Links:
Coronavirus (COVID-19) (NIH)
Camille Ehre (University of North Carolina, Chapel Hill)
Posted In: Snapshots of Life
Tags: cilia, COPD, coronavirus, COVID-19, cystic fibrosis, imaging, lungs, mucus, novel coronavirus, pandemic, SARS-CoV-2, SARS-CoV-2 transmission, scanning electron microscopy, SEM, viral particles
How Mucus Tames Microbes
Posted on December 19th, 2019 by Dr. Francis Collins
Credit: Katharina Ribbeck, Massachusetts Institute of Technology, Cambridge
Most of us think of mucus as little more than slimy and somewhat yucky stuff that’s easily ignored until you come down with a cold like the one I just had. But, when it comes to our health, there’s much more to mucus than you might think.
Mucus covers the moist surfaces of the human body, including the eyes, nostrils, lungs, and gastrointestinal tract. In fact, the average person makes more than a liter of mucus each day! It houses trillions of microbes and serves as a first line of defense against the subset of those microorganisms that cause infections. For these reasons, NIH-funded researchers, led by Katharina Ribbeck, Massachusetts Institute of Technology, Cambridge, are out to gain a greater understanding of the biology of healthy mucus—and then possibly use that knowledge to develop new therapeutics.
Ribbeck’s team used a scanning electron microscope to take the image of mucus you see above. You’ll notice right away that mucus doesn’t look like simple slime at all. In fact, if you could zoom into this complex web, you’d discover it’s made up of mucin proteins and glycans, which are sugar molecules that resemble bottle brushes.
Ribbeck and her colleagues recently discovered that the glycans in healthy mucus play a long-overlooked role in “taming” bacteria that might make us ill [1]. This work builds on their previous findings that mucus interferes with bacterial behavior, preventing these bugs from attaching to surfaces and communicating with each other [2].
In their new study, published in Nature Microbiology, Ribbeck, lead author Kelsey Wheeler, and their colleagues studied mucus and its interactions with Pseudomonas aeruginosa. This bacterium is a common cause of serious lung infections in people with cystic fibrosis or compromised immune systems.
The researchers found that in the presence of glycans, P. aeruginosa was rendered less harmful and infectious. The bacteria also produced fewer toxins. The findings show that it isn’t just that microbes get trapped in a tangled web within mucus, but rather that glycans have a special ability to moderate the bugs’ behavior. The researchers also have evidence of similar interactions between mucus and other microorganisms, such as those responsible for yeast infections.
The new study highlights an intriguing strategy to tame, rather than kill, bacteria to manage infections. In fact, Ribbeck views mucus and its glycans as a therapeutic gold mine. She hopes to apply what she’s learned to develop artificial mucus as an anti-microbial therapeutic for use inside and outside the body. Not bad for a substance that you might have thought was nothing more than slimy stuff.
References:
[1] Mucin glycans attenuate the virulence of Pseudomonas aeruginosa in infection. Wheeler KM, Cárcamo-Oyarce G, Turner BS, Dellos-Nolan S, Co JY, Lehoux S, Cummings RD, Wozniak DJ, Ribbeck K. Nat Microbiol. 2019 Oct 14.
[2] Mucins trigger dispersal of Pseudomonas aeruginosa biofilms. Co JY, Cárcamo-Oyarce, Billings N, Wheeler KM, Grindy SC, Holten-Andersen N, Ribbeck K. NPJ Biofilms Microbiomes. 2018 Oct 10;4:23.
Links:
Cystic Fibrosis (National Heart, Lung, and Blood Institute/NIH)
Video: Chemistry in Action—Katharina Ribbeck (YouTube)
Katharina Ribbeck (Massachusetts Institute of Technology, Cambridge)
NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Envir_o_nmental Health Sciences; National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases
Posted In: Snapshots of Life
Tags: artificial mucus, bacteria, cystic fibrosis, eyes, gastrointestinal tract, glycans, immunity, infection, lungs, microbiology, mucin, mucus, nose, Pseudomonas aeruginosa