Imagine the worst cold you've ever had in your life. Your nose feels completely blocked. You struggle for air. The pressure in your sinuses sends pain streaking around your head. You can't smell, so eating food is like chewing on cardboard, you are nauseated and you feel utterly miserable. Now imagine that the symptoms, even if they ease for a week or so, always come back. You are never free. Ever.
Unfortunately, this is the very real life of patients with chronic sinusitis—technically called chronic rhinosinusitis—a disease of the nose and other regions of the upper airway that affects about 35 million Americans. For many of these people, treatment often involves prolonged courses of antibiotics and steroids. If those drugs do not work, sufferers have to undergo delicate surgery to clean out infected cavities in their skull. This surgery seems to be happening more often these days because modern society's excessive use of antibiotics has perversely caused those medications to become less effective. Today one out of every five antibiotic prescriptions in the U.S. is for an adult with rhinosinusitis, and the illness has become part of a vicious cycle, contributing to the rise of such dangerous antibiotic-resistant bacteria as methicillin-resistant Staphylococcus aureus (MRSA).
That's where we come into this story. We want to break the cycle. Along with many other researchers, we are working to understand the immune defense mechanisms that cells on the inner surface of the airway, known as epithelial cells, deploy against respiratory infections. The average person breathes in more than 10,000 liters of air a day, much of it through the nose, and that air contains countless bacteria, fungi and viruses. Our nose is the front line of respiratory defense. Every time we breathe, particles of debris, viruses, bacteria and fungal spores get trapped there. Yet amazingly, most people walk around breathing freely without any kind of airway infection.
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It turns out that one previously unsuspected reason may be, literally, on our tongue. Proteins there—called taste receptors—that detect bitter flavors have been found to do double duty, also defending us against bacteria. Our own research has shown that these receptors, also found in the nose, trigger three bacteria-fighting responses. First, they send signals that cause the cells to flick invaders away by moving cilia—tiny, hairlike projections—on the cells' surface. Second, the receptor proteins tell cells to release nitric oxide, which kills bacteria. Third, receptors signal still other cells to send out antimicrobial proteins called defensins.
Even more astonishing, several researchers have found these receptors not just on the tongue and nose but elsewhere in the airway, as well as in the heart, lungs, intestines and more body organs. Along with other scientists, we now believe these receptors are part of an innate human immune system that is different—but potentially faster—than the more familiar features of antibodies and invader-fighting cells that circulate through our body. It can take many hours or days for the immune system to produce specific antibodies against viruses or bacteria. The taste receptor responses, though more of a general reaction and less tightly targeted to particular bacteria, happen in just minutes—a true early-warning system.
A taste for danger
If you think of taste receptors as sentinels that react to substances that come into the body, then their immune system role makes sense. When they reside on the cells that form taste buds on the tongue, the receptors prompt the cells to send signals to the brain that tell it about the nutritional value or potential toxicity of the foods we put in our mouth. The tongue detects five basic types of tastes: bitter, sweet, salty, sour and savory, also known as umami. Our sense of taste acts as the gatekeeper to the digestive system, giving us information about the food we are eating so that we can decide whether or not to swallow it. Bitter taste receptors can detect the presence of poisonous plant chemicals, including a class of chemicals called alkaloids that includes strychnine and nicotine. The tastes we today describe as “bitter” are often perceived by our brain as unpleasant because receptors evolved to signal the presence of potentially harmful chemicals.
Warning against harm is key to survival, which may be why there are so many different bitter receptors. Sweet, salty, sour and umami have only one type of receptor each, but at least 25 types of receptors detect bitter compounds. Known as taste family type 2 receptors, or T2Rs, they probably evolved to recognize and protect us from swallowing a wide variety of poisons.
Early hints of a role elsewhere in the body emerged in 2009, when researchers at the University of Iowa discovered T2Rs on epithelial cells that line the lungs. A sticky layer of mucus on top of these cells traps microbes and irritants when we inhale them. Then the tiny cilia on the cells beat eight to 15 times each second, in synchrony, to push the irritants toward the throat, where you swallow them or spit them out. The Iowa team discovered that cilia in human lung cells actually beat faster when their T2Rs were stimulated by bitter compounds, suggesting that the T2Rs help the airway clear potentially dangerous inhaled substances that, in the mouth, would taste bitter.
Around the same time, investigators at the University of Colorado Anschutz Medical Campus were studying bitter taste receptors found on a special type of cell in the rat nose that appears to react to irritants. They discovered that these cells, termed solitary chemosensory cells, become more active when they detect bacterial molecules called acyl-homoserine lactones (AHLs). AHLs are released by dangerous gram-negative bacteria when these microbes form biofilms. Biofilms are communities of bacteria, such as Pseudomonas aeruginosa, that stick to one another by forming a matrix, making them up to 1,000-fold more resistant to antibiotics than less organized bacteria are and thus much harder to kill. The researchers from Colorado showed the biofilm-inducing AHL molecules stimulated activity in the chemosensory cells. AHLs were thus the first specific bacterial chemical shown to stimulate cells with bitter taste receptors, supporting the notion that receptors respond to outside invaders.
Intrigued by these findings, we began searching for taste receptors in human nasal epithelial cells in 2011, collaborating with experts in taste at the Monell Chemical Senses Center in Philadelphia, a premier institution for smell and taste research. Our investigation started out as a small side project to determine whether we could find bitter taste receptors in nasal cells just as the Iowa researchers found them in the lung. But it quickly became a big focus in our laboratory when we saw hints that certain taste receptors might affect people's susceptibility to rhinosinusitis.
Supertasters
In our search, we looked specifically for one bitter taste receptor, T2R38, the most well studied of the T2R family. The human T2R38 protein comes in several varieties, the result of slight differences, called polymorphisms, in the genes that encode them. And we did find many of the most common versions in the cilia lining the nose and sinuses.
The discovery of this receptor menagerie led us to explore how the different T2R38 forms affect the behavior of sinus and nasal cells. Two forms in particular have dramatically different effects on taste when present in the tongue. One of these versions is very sensitive as a taste detector in the mouth, and the other one does not respond at all. About 30 percent of Caucasians inherit two copies of the gene for the insensitive T2R38 variant (one from each parent), and these individuals are “nontasters” for certain bitter compounds. About 20 percent of Caucasians have two copies of the gene for the functional T2R38, and these individuals perceive those same compounds as intensely bitter; such people are known as “supertasters.” Those with one copy of each gene variant fall somewhere in between these extremes.
Examining tissue removed during sinus and nasal surgeries, we compared the behaviors of nasal cells possessing one or the other of these two forms. (We knew which types were in the cells by sequencing their genes.) To get the receptors to react, we exposed the cells to a chemical called phenylthiocarbamide (PTC), often used for T2R38 taste testing. And we were excited to see that the cells from supertaster patients, but not those from the nontasters, produced large amounts of nitric oxide.
This finding gave another boost to our idea of a taste-immunity connection. Nitric oxide does two important things against bacteria in the airway. It can stimulate airway cells to increase ciliary beating. It can also directly kill bacteria. Because nitric oxide molecules form a gas, they can rapidly diffuse out of the cells lining the airway into the mucus and then into bacteria. Once inside, the substance can damage membranes, enzymes and DNA. Ordinarily our sinuses produce large amounts of nitric oxide that travel through the airway, which helps to keep it free of infection.
These twin modes of antibacterial activity made us think that different T2R38 versions might alter people's susceptibility to upper respiratory infections. And indeed, in the lab, we found that the nitric oxide produced by supertaster nasal cells during T2R38 activation caused faster ciliary beating and directly killed more bacteria than nontaster nasal cells. We next discovered that the same class of bacterial compounds that were previously shown to activate mouse nasal chemosensory cells, AHLs, directly activates human T2R38 receptors. Nasal cells from supertasters detect bacterial AHLs through T2R38 and produce nitric oxide, whereas cells from nontasters do not. These properties make cells from supertasters much better at killing AHL-producing bacteria than cells from nontasters. From these observations, we concluded that the T2R38 bitter receptor is used by airway epithelial cells to detect bacterial activity and activate defenses.
Since our discovery of T2R38 in cilia of human nasal epithelial cells, our knowledge of the role of taste receptors in the nose has expanded even further. These receptors also appear in solitary chemosensory cells in the human nose, similar to those found in mice. Solitary chemosensory cells really are solitary, dispersed widely throughout the nasal cavity and making up about only 1 percent of the cells there. The cells have both T2R bitter receptors and T1R sweet receptors. When T2Rs in these cells get stimulated, we have found, the solitary cells release a signal to surrounding cells that prompts them to release antimicrobial proteins called defensins into the airway mucus. Defensins are capable of killing many illness-causing bacteria, including P. aeruginosa and MRSA.
The sweet taste receptors, when stimulated, shut down the activity of the bitter ones, probably to prevent cells from releasing too many proteins at an inappropriate time. Sweet receptors had already been found in other body parts, such as the pancreas, where they sense sugars in the blood and stimulate cells to produce insulin that regulates glucose levels. Our work on the nasal cells, however, showed that sweet and bitter receptors in the same cell have opposing roles.
These experiments suggest to us that taste receptors constitute an early-warning arm of the airway immune response. They seem different from the most well-studied class of early-warning proteins, which are known as toll-like receptors (TLRs). The TLRs also activate immune responses when stimulated by certain bacterial molecules, as the T2Rs appear to do. But there is at least one important difference: some TLR responses—such as signaling genes to start creating antibodies that mark invaders for destruction—are much slower, taking several hours or even days. T2R38 and its bitter cousins, in contrast, produce responses within seconds to minutes. These taste receptors might be most important during the onset of infection by activating a kind of “locked and loaded” instant reaction. Other immune receptors may be more crucial for fighting a prolonged infection, calling up the troops when the first response is not sufficient.
Vulnerable people
The large number of genetic varieties in T2R bitter taste receptors makes their role in immunity even more intriguing. Most of the 25 bitter receptors have genetic variations that increase or decrease their abilities, thus making people who have them more or less sensitive to bitter-tasting substances. If a reaction to bitterness is indeed part of the immune response to invading bacteria, these same genetic variations may also create differences in the way people combat infections. Increased bitter receptor function may confer greater protection against infection, whereas lower function may increase susceptibility.
We have begun to test this idea in people and have hints that it is correct. The millions of patients with chronic rhinosinusitis constitute a natural test population and a group in need of help. When given quality-of-life questionnaires, rhinosinusitis patients report worse scores than patients with several heart and lung diseases. Plus, rhinosinusitis patients can develop dangerous lung infections and exacerbate lower airway diseases such as asthma. We have looked at microbiology cultures from patients with the condition. Supertasters did get rhinosinusitis—they are not immune—but they had a much lower frequency of nasal infections with gram-negative bacteria than did nontasters. That makes sense because gram-negative bacteria produce AHLs, the compounds that, by triggering receptors, lead cells in these people to release microbe-killing nitric oxide. Other bacteria do not produce AHL, so they would not run afoul of these immune defenses.
Further clinical research has supported the role of T2R38 in sinusitis. Two studies from our group at Pennsylvania demonstrated that people with two copies of the T2R38 supertaster gene are less likely to get severe rhinosinusitis than are patients with two nontaster copies or even patients with one copy of each. A study by otolaryngologist Martin Desrosiers of CHUM in Montreal and his colleagues verified that the T2R38 nontaster gene occurs more often in patients than in healthy people. That study found that rhinosinusitis severity is also associated with variants in two other T2R receptor types, T2R14 and T2R49.
In organs beyond the nose, connections between taste receptors and immunity are starting to show up. In 2014 scientists showed that when confronted with pathogenic Escherichia coli, chemosensory cells in the urinary tract use T2Rs to stimulate the bladder to release urine. This could be the body trying to flush bacteria out and prevent bladder infections. Another recent study has shown that white blood cells—which include neutrophils and lymphocytes and are crucial components of the immune system—also use T2R38 to detect Pseudomonas AHLs.
Right now we want to learn whether chemicals that activate T2R receptors can work as medicine for rhinosinusitis patients by stimulating stronger bacteria-killing responses. The vast array of bitter compounds in foods we eat and drink every day could be potential therapeutics, including humulones and lupulons from hoppy beers, isothiocyanates from green vegetables such as Brussels sprouts and bitter chemicals from citrus such as limonin. Absinthin, a bitter chemical isolated from the wormwood plant and found in the liquor absinthe, has been shown to stimulate solitary chemosensory cell T2Rs. In our lab, we are investigating several formulations that could work as drugs. Novel medications based on bitter compounds might someday be used to combat infection without using conventional antibiotics.
We believe it is also possible that taste or genetic testing of T2Rs might eventually be used to predict susceptibility to infections. The natural variations in these taste receptors may help us answer an age-old question: Why do some people frequently get respiratory infections, whereas others never seem to get sick? Using bitter receptors to solve this puzzle would be sweet indeed.