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Published On August 1, 2019

BASIC RESEARCH

A Secret Sense

Receptors that can smell and taste exist throughout the body. Can they be allies in learning to fight disease?

Nutrient receptors—a class of proteins that help an organism know what’s safe to eat—go back billions of years on the evolutionary tree. Even the most basic organisms sport these receptors on the outside of their cell walls, and in mammals they exist in great profusion on the cells of the nose and tongue.

Their specialized functions—in the case of human taste buds, detecting the presence of a molecule that is sweet, salty, sour, bitter or savory—led researchers to believe their role in the body was limited to those areas. But over the past decade, the proteins have turned up in many different tissues, and seem to play a role in tasks as diverse as breathing and regulating blood pressure. This has led some researchers to explore whether the receptors might be nudged to do something useful—for instance, to help treat disease.

The science of taste receptors is fairly recent, and the first ones to be discovered—bitter and sweet—were identified only in 2000 and 2001, respectively. How they perform their functions in the nose and mouth is still something of a mystery. Receptors on taste buds, for instance, appear to bind with a molecule that matches their shape, which sets off a chemical cascade that ultimately sends an impulse through nerve cells to the brain.

But their discovery in other parts of the body—sweet taste receptors in the gut, for instance, found in 2007, as well as discoveries of receptors in the lungs, heart, liver and testes—pointed to a more versatile role, including cellular communication using sweet and bitter compounds, says University of Pennsylvania otolaryngologist Noam Cohen, who is looking at their role in the respiratory system.

Cohen has been working with a bitter taste receptor named T2R38, which responds to the chemical phenylthiocarbamide (PTC). On the tongue, activation of T2R38 by PTC leads to a “yuck” response—a conscious revulsion. In the nose and sinuses, however, the bitter receptors don't send signals to the brain. Cohen thought they might be “tasting” a different type of foreign body—pathogens—and triggering a local response.

He found that when T2R38 detected PTC, it caused the nasal cells to release nitric oxide gas, which caused the cilia to beat more quickly, a key step in warding off infection and flushing bacteria out of the airways. The gas also diffused into the mucus and killed some bacteria and prevented other types from replicating. Cohen then looked at people who carry a specific version of T2R38 that makes them “supertasters,” able to detect PTC at extremely low concentrations on their tongues. Supertasters also rarely got sinus infections from particular bacteria. When Cohen cultured their nasal cells, he found that the super-sensitive T2R38 receptor triggered a strong response to even the weakest presence of the pathogen Pseudomonas aeruginosa—releasing nitric oxide and beating their cilia.

“These receptors allow cells to ‘taste’ the mucus in the airway to determine if bacteria are present. If you’re a supertaster, it seems that you can ‘taste’ certain bacterial secretions at super low concentrations, which lets the body turn on its immune defenses really early,” Cohen says.

In January 2019, Cohen showed that one existing therapy, an immunostimulant called Broncho-Vaxom that is used outside of the United States to treat bronchitis, appeared to work by activating bitter taste receptors. The medicine stimulated the beating of cilia that swept bacteria out of the airway. That finding led him to believe that work with nutrient receptors might lead to better diagnostics and treatments.

In March, Andrew Vaughan, a professor of biomedical science at the University of Pennsylvania School of Veterinary Medicine, worked with Cohen to show that a severe bout of influenza in mice caused “tuft cells,” which are sensitive to certain chemicals, to grow in the lungs. Researchers found that these particular tuft cells responded to bitter compounds, meaning that they had nutrient receptors, and that triggering them led to an inflammatory response, which may be a mechanism to help speed recovery but could also be a driver of futher disease, such as asthma. Learning to manipulate these tuft cells might help treat respiratory infections without antibiotics or antivirals, Cohen says.

Research is also advancing on nutrient receptors found elsewhere in the body. In 2014, German scientists identified the olfactory receptor OR2AT4 in skin cells, then discovered that stimulating this receptor with a synthetic sandalwood scent caused epidermal cells to proliferate and migrate—an important step in wound healing. And in September 2018, University of Miami dermatology scientist Jérémy Chéret and colleagues also found OR2AT4 in hair follicles. When the researchers cultured the follicles and treated them with the scent, it increased release of a growth factor and lengthened the time follicles spent growing the hair shaft before it died and fell out. Chéret says that activating this receptor could help people fight hair loss. “We had assumed we wouldn’t find these receptors outside the nose,” Chéret says. “But every day, it seems we are finding another role for these olfactory receptors.”

To Peihua Jiang, a neurobiologist at the Monell Chemical Senses Center in Philadelphia who has watched the field develop, these findings are only the beginning. “Once we really understand which receptor responds to what molecule, we can have some really good drug targets,” Jiang says. “I believe we can learn how to harness these avenues to treat disease.”