How Mucus Tames Microbes
Posted on by Dr. Francis Collins
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 . 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 .
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.
 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.
 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.
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 Environmental Health Sciences; National Institute of General Medical Sciences; National Institute of Allergy and Infectious Diseases
A Nose for Science
Posted on by Dr. Francis Collins
Our nose does a lot more than take in oxygen, smell, and sometimes sniffle. This complex organ also helps us taste and, as many of us notice during spring allergy season when our noses get stuffy, it even provides some important anatomic features to enable us to speak clearly.
This colorful, almost psychedelic image shows the entire olfactory epithelium, or “smell center,” (green) inside the nasal cavity of a newborn mouse. The olfactory epithelium drapes over the interior walls of the nasal cavity and its curvy bony parts (red). Every cell in the nose contains DNA (blue).
The olfactory epithelium detects odorant molecules in the air, providing a sense of smell. In humans, the nose has about 400 types of scent receptors, and they can detect at least 1 trillion different odors .
But this is more than just a cool image captured by graduate student Lu Yang, who works with David Ornitz at Washington University School of Medicine, St. Louis. The two discovered a new type of progenitor cell, called a FEP cell, that has the capacity to generate the entire smell center . Progenitor cells are made by stem cells. But they are capable of multiplying and producing various cells of a particular lineage that serve as the workforce for specialized tissues, such as the olfactory epithelium.
Yang and Ornitz also discovered that the FEP cells crank out a molecule, called FGF20, that controls the growth of the bony parts in the nasal cavity. This seems to regulate the size of the olfactory system, which has fascinating implications for understanding how many mammals possess a keener sense of smell than humans.
But it turns out that FGF20 does a lot more than control smell. While working in Ornitz’s lab as a postdoc, Sung-Ho Huh, now an assistant professor at the University of Nebraska Medical Center, Omaha, discovered that FGF20 helps form the cochlea . This inner-ear region allows us to hear, and mice born without FGF20 are deaf. Other studies show that FGF20 is important for development of the kidney, teeth, mammary gland, and of specific types of hair [4-7]. Clearly, this indicates multi-tasking can be a key feature of a protein, not a trivial glitch.
The image was one of the winners in the 2018 BioArt Scientific Image & Video Competition, sponsored by the Federation of American Societies for Experimental Biology (FASEB). Its vibrant colors help to show the basics of smell, and remind us that every scientific picture tells a story.
 Humans can discriminate more than 1 trillion olfactory stimuli. Bushdid C1, Magnasco MO, Vosshall LB, Keller A. Science. 2014 Mar 21;343(6177):1370-1372.
 FGF20-Expressing, Wnt-Responsive Olfactory Epithelial Progenitors Regulate Underlying Turbinate Growth to Optimize Surface Area. Yang LM, Huh SH, Ornitz DM. Dev Cell. 2018;46(5):564-580.
 Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal. Huh SH, Jones J, Warchol ME, Ornitz DM. PLoS Biol. 2012;10(1):e1001231.
 FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Barak H, Huh SH, Chen S, Jeanpierre C, Martinovic J, Parisot M, Bole-Feysot C, Nitschke P, Salomon R, Antignac C, Ornitz DM, Kopan R. Dev. Cell. 2012;22(6):1191-1207
 Ectodysplasin target gene Fgf20 regulates mammary bud growth and ductal invasion and branching during puberty. Elo T, Lindfors PH, Lan Q, Voutilainen M, Trela E, Ohlsson C, Huh SH, Ornitz DM, Poutanen M, Howard BA, Mikkola ML. Sci Rep. 2017;7(1):5049
 Ectodysplasin regulates activator-inhibitor balance in murine tooth development through Fgf20 signaling. D Haara O, Harjunmaa E, Lindfors PH, Huh SH, Fliniaux I, Aberg T, Jernvall J, Ornitz DM, Mikkola ML, Thesleff I. Development. 2012;139(17):3189-3199.
 Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles. Huh SH, Närhi K, Lindfors PH, Häärä O, Yang L, Ornitz DM, Mikkola ML. Genes Dev. 2013;27(4):450-458.
Taste and Smell (National Institute on Deafness and Other Communication Disorders/NIH)
Ornitz Lab, (Washington University, St. Louis)
Huh Lab, (University of Nebraska Medical Center, Omaha)
BioArt Scientific Image & Video Competition, (Federation of American Societies for Experimental Biology, Bethesda, MD)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute on Deafness and Other Communication Disorders
These Oddball Cells May Explain How Influenza Leads to Asthma
Posted on by Dr. Francis Collins
Most people who get the flu bounce right back in a week or two. But, for others, the respiratory infection is the beginning of lasting asthma-like symptoms. Though I had a flu shot, I had a pretty bad respiratory illness last fall, and since that time I’ve had exercise-induced asthma that has occasionally required an inhaler for treatment. What’s going on? An NIH-funded team now has evidence from mouse studies that such long-term consequences stem in part from a surprising source: previously unknown lung cells closely resembling those found in taste buds.
The image above shows the lungs of a mouse after a severe case of H1N1 influenza infection, a common type of seasonal flu. Notice the oddball cells (green) known as solitary chemosensory cells (SCCs). Those little-known cells display the very same chemical-sensing surface proteins found on the tongue, where they allow us to sense bitterness. What makes these images so interesting is, prior to infection, the healthy mouse lungs had no SCCs.
SCCs, sometimes called “tuft cells” or “brush cells” or “type II taste receptor cells”, were first described in the 1920s when a scientist noticed unusual looking cells in the intestinal lining  Over the years, such cells turned up in the epithelial linings of many parts of the body, including the pancreas, gallbladder, and nasal passages. Only much more recently did scientists realize that those cells were all essentially the same cell type. Owing to their sensory abilities, these epithelial cells act as a kind of lookout for signs of infection or injury.
This latest work on SCCs, published recently in the American Journal of Physiology–Lung Cellular and Molecular Physiology, adds to this understanding. It comes from a research team led by Andrew Vaughan, University of Pennsylvania School of Veterinary Medicine, Philadelphia .
As a post-doc, Vaughan and colleagues had discovered a new class of cells, called lineage-negative epithelial progenitors, that are involved in abnormal remodeling and regrowth of lung tissue after a serious respiratory infection . Upon closer inspection, they noticed that the remodeling of lung tissue post-infection often was accompanied by sustained inflammation. What they didn’t know was why.
The team, including Noam Cohen of Penn’s Perelman School of Medicine and De’Broski Herbert, also of Penn Vet, noticed signs of an inflammatory immune response several weeks after an influenza infection. Such a response in other parts of the body is often associated with allergies and asthma. All were known to involve SCCs, and this begged the question: were SCCs also present in the lungs?
Further work showed not only were SCCs present in the lungs post-infection, they were interspersed across the tissue lining. When the researchers exposed the animals’ lungs to bitter compounds, the activated SCCs multiplied and triggered acute inflammation.
Vaughan’s team also found out something pretty cool. The SCCs arise from the very same lineage of epithelial progenitor cells that Vaughan had discovered as a post-doc. These progenitor cells produce cells involved in remodeling and repair of lung tissue after a serious lung infection.
Of course, mice aren’t people. The researchers now plan to look in human lung samples to confirm the presence of these cells following respiratory infections.
If confirmed, the new findings might help to explain why kids who acquire severe respiratory infections early in life are at greater risk of developing asthma. They suggest that treatments designed to control these SCCs might help to treat or perhaps even prevent lifelong respiratory problems. The hope is that ultimately it will help to keep more people breathing easier after a severe bout with the flu.
 Closing in on a century-old mystery, scientists are figuring out what the body’s ‘tuft cells’ do. Leslie M. Science. 2019 Mar 28.
 Development of solitary chemosensory cells in the distal lung after severe influenza injury. Rane CK, Jackson SR, Pastore CF, Zhao G, Weiner AI, Patel NN, Herbert DR, Cohen NA, Vaughan AE. Am J Physiol Lung Cell Mol Physiol. 2019 Mar 25.
 Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, Tan K, Tan V, Liu FC, Looney MR, Matthay MA, Rock JR, Chapman HA. Nature. 2015 Jan 29;517(7536):621-625.
Asthma (National Heart, Lung, and Blood Institute/NIH)
Influenza (National Institute of Allergy and Infectious Diseases/NIH)
Vaughan Lab (University of Pennsylvania, Philadelphia)
Cohen Lab (University of Pennsylvania, Philadelphia)
Herbert Lab (University of Pennsylvania, Philadelphia)
NIH Support: National Heart, Lung, and Blood Institute; National Institute on Deafness and Other Communication Disorders
Navigating the Sense of Smell
Posted on by Dr. Francis Collins
Our ability to distinguish the aroma of freshly baked bread from the sweet fragrance of a rose comes from millions of sensory neurons that line the upper nasal cavity. These so-called olfactory sensory neurons activate when the specific types of odor molecules to which they are attuned enter the nose, prompting them to send their sensory alerts onward to the brain, where we become aware of a distinctive scent.
If you look closely at the striking image above from a young mouse, the thin, fluorescently labeled lines (red, green, white) show the neuronal extensions, or axons, of olfactory sensory neurons. These information-conveying axons stretch right to left from the nose through the smell-mediating olfactory bulb (blue) in the forebrain of all vertebrates, ending in just the right spot (white, pink, or red).
But the axons presented here don’t belong to just any olfactory sensory neurons. They represent newly discovered “navigator” neurons, which are essential to forge life’s very first olfactory connections .
The image comes from a recent paper in the journal Neuron from an NIH-supported team led by C. Ron Yu, Stowers Institute for Medical Research, Kansas City, MO. Yu’s team offered the first hints of navigator neurons a few years ago when it showed that young mice could correct errors in their olfactory wiring only when those disruptions occurred within the first week of life .
After that, the mice had lifelong abnormalities in their sense of smell. The findings suggested that the olfactory sensory neurons present very early in life had a unique ability to blaze a trail to the brain to establish a coherent olfactory map.
The new study confirms that navigator neurons indeed have a unique molecular identity. During their short lives, they show more extensive axon growth compared to neurons that arise later. Their axons also travel a more circuitous route to the brain, as if exploring the neural tissue before settling on a path to their final destination. As olfactory neurons in older mice regenerate, they simply follow the trail blazed for them by those early scouts.
While the new findings involve mice, the researchers suspect similar processes are at work in humans too. That means images like this one aren’t just fascinating. They could help pave the way toward new approaches for reviving navigator neurons, potentially making it possible to forge new olfactory connections—and bring back the enjoyment of delightful aromas such as freshly baked bread or roses—in those who’ve lost the ability to smell.
 A population of navigator neurons is essential for olfactory map formation during the critical period. Wu Y, Ma L, Duyck K, Long CC, Moran A, Scheerer H, Blanck J, Peak A, Box A, Perera A, Yu CR. Neuron. 2018 Dec 5;100(5):1066-1082.
 A developmental switch of axon targeting in the continuously regenerating mouse olfactory system. Ma L, Wu Y, Qiu Q, Scheerer H, Moran A, Yu CR. Science. 2014 Apr 11;344(6180):194-197.
Smell Disorders (National Institute on Deafness and Other Communication Disorders)
Yu Lab (Stowers Institute for Medical Research, Kansas City, MO)
NIH Support: National Institute on Deafness and Other Communication Disorders
Possible Explanation for Why Some People Get More Colds
Posted on by Dr. Francis Collins
Colds are just an occasional nuisance for many folks, but some individuals seem to come down with them much more frequently. Now, NIH-funded researchers have uncovered some new clues as to why.
In their study, the researchers found that the cells that line our airways are quite adept at defending against cold-causing rhinoviruses. But there’s a tradeoff. When these cells are busy defending against tissue damage due to cigarette smoke, pollen, pollutants, and/or other airborne irritants, their ability to fend off such viruses is significantly reduced .
The new findings may open the door to better strategies for preventing the common cold, as well as other types of respiratory tract infections caused by non-flu viruses. Even small improvements in prevention could have big implications for our nation’s health and economy. Every year, Americans come down with more than 500 million colds and similar infections, leading to reduced work productivity, medical expenses, and other costs approaching $40 billion .