A Line of Defense Hidden Inside the Nose

This article was written by Mike Kotsopoulos and republished from the Spring 2023 Harvard Otolaryngology Magazine.

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The common cold disrupts millions of lives every winter. According to the Centers for Disease Control and Prevention, an American adult, on average, contracts a cold two-to-three times a year, and American children are infected at a rate even higher. The sore throat, runny nose, coughing, aches, and pains of a typical cold can last for days and, in particularly bad cases, are enough to keep adults and children home from work and school, respectively.

For years, the viruses responsible for colds followed a trend that bewildered clinicians and epidemiologists alike. Upper respiratory infections (URIs) from these viruses, as well as those from the flu and COVID-19, would occur in significantly higher frequencies during cold seasons.

Researchers suspected that cold weather played a significant role in the seasonal variation of URIs. However, they could never point to an exact reason why. Many speculated that colder weather forced people indoors for longer periods of time, allowing viruses to spread from person to person with great ease. Even so, such an explanation overlooked a critical trend of modern, first-world nations.

"Regardless of the season, people in America and other developed nations are spending more time than ever indoors, whether it's at work, playing sports, or relaxing with family," said Benjamin S. Bleier, MD, FACS, professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School and director of Otolaryngology Translational Research at Mass Eye and Ear. "If we're spending so much more time indoors year-round, then why haven't we seen similar spikes in URIs during warmer months year-to-year?"

The correlation between URIs and cold weather remained a mystery until 2022, when Dr. Bleier, Mass Eye and Ear Investigator Di Huang, PhD, and collaborators from the laboratory of Mansoor Amiji, PhD, at Northeastern University uncovered a previously unidentified immune response to viruses at the front of the nose. Published in The Journal of Allergy and Clinical Immunology, their findings are the first to quantitatively demonstrate how cold temperatures impair the ability of the nose to defend against seasonal respiratory viruses.

Since then, the uncovered missing link has galvanized the worldwide scientific community, captivating scientists with the possibility of harnessing the newfound immune response to fight a wide array of airborne diseases.

Setting a Trap

The immune system relies on two types of immunity to fight disease: adaptive and innate. Adaptive immunity is a trained response to a new group of pathogens. Through vaccination or natural exposure, the body gradually builds the antibodies necessary to defend itself from pathogens. Innate immunity, on the other hand, is an evolutionary, built-in response to a broad group of pathogens. During such a response, the body immediately recognizes a pathogen and uses preexisting antibodies to activate pathways that generate an instantaneous reaction.

The earliest signs of an innate immune response inside the nose were uncovered by Dr. Bleier and Dr. Amiji, distinguished professor of Pharmaceutical Sciences at Northeastern University, in 2018. Together, the researchers introduced bacteria to live nasal tissue samples and observed millions of tiny particles—called extracellular vesicles (EVs)—swarming around the pathogen. Published in The Journal of Allergy and Clinical Immunology, their early observations revealed that nasal epithelial cells from the front of the nose had detected the bacteria and released the EVs, each of which carried molecules specially designed to neutralize the bacteria.

"Imagine swarms of angry hornets attacking someone who hits their nest," said Dr. Bleier. "The immune system rarely, if ever, releases a response outside its own body to attack a pathogen, and we immediately wondered if a similar response might occur against viruses."

In 2022, Drs. Bleier, Huang and Amiji tested the uncovered immune response against three of the most common seasonal respiratory viruses—a single coronavirus and two rhinoviruses. According to their most recent findings published in The Journal of Allergy and Clinical Immunology, the viruses triggered similar swarms of EVs when introduced to live human tissue samples in vitro. But not without a unique twist. The EVs had met the viruses with a second line of defense unseen against bacteria: decoys.

Each EV carried special receptors resembling those on the surface of nasal epithelial cells. Unlike bacteria, viruses can only invade a cell if spike proteins on its exterior are attached to unique receptors on a cell's surface. By confronting the viruses with millions of receptors indiscernible from those on the surface of the targeted cells, the EVs set an elaborate trap. The viruses mistook the receptors on the EVs for their intended targets. Once the viruses latched onto the decoys, the EVs used packaged strands of microRNA to disable the pathogens.

"Think of the viruses like burglars trying to break into a home," explained Dr. Huang. "Except, instead of arriving at their destination, the viruses encounter millions of booby-trapped homes identical to their target."

Freezing the Defense

Few areas of the body are more sensitive to their environment than the front of the nose. According to Dr. Bleier, approximately 10,000 liters of air are inhaled through the nose each day. With each breath inhaled, countless airborne pathogens are caught by mucus at the front of the nose, where only a few minutes of direct exposure to cold air can decrease its internal temperature by several degrees. Unlike the deeper nasal cavity, where specialized structures provide higher amounts of surface area to humidify air, the front of the nose cannot regulate abrupt changes to air temperature on its own, making it especially susceptible to colder air.

To determine how temperature might affect the observed immune response to airborne viruses, Dr. Bleier and his team decided to quantify temperature reductions at the front of the nose in cold, ambient environments. The researchers began by exposing healthy volunteers at room temperature to temperatures at 4.4° C. Then, after 15 minutes, the researchers used an endoscope and thermocouple to determine a temperature drop of about 5° C in their anterior nasal cavities. The temperature difference was then applied to in vitro samples of nasal tissues, which were subsequently exposed to the researchers' original trio of respiratory viruses.

Observations from the preclinical study revealed that the total amount of EVs had decreased by at least 40% at colder temperatures compared to the total released at room temperature. Each released EV appeared less capable of defending the nose, too. The number of special receptors used as decoys against the viruses had decreased by 77%, and the number of microRNA strands used to neutralize the viruses had decreased by at least a quarter.

While the observations still required the validation of a definitive clinical trial, Dr. Bleier knew the study had unveiled something extraordinary.

"It was as if a switch had been flipped," he said. "Just a five-degree drop in temperature was enough to double the likelihood of viruses infecting nasal epithelial cells, replicating inside those cells and infecting neighboring tissue deeper in the body."

Augmenting Optimal Responses

For each new part of the immune system uncovered, an intriguing opportunity can present itself. Discovering how temperature affects the immune response has encouraged Drs. Huang and Bleier to imagine a wide range of therapeutics capable of recreating and augmenting the nose's innate defense mechanism. Ideally, therapeutics might strengthen response potency by increasing the amount of EVs released from nasal epithelial cells or increasing the number of microRNAs and special protein receptors carried by each EV.

Existing drugs delivered to the front of the nose, such as topical nasal sprays, have made the prospect of future therapeutics even more tangible. The complexity of any therapeutic research, however, hinges on whether scientists can learn how to initiate or maintain the desired innate immune response over an extended period of time without jeopardizing its safety or effectiveness.

At Mass Eye and Ear, Drs. Huang and Bleier are currently researching the specific microRNA strands found inside antiviral EVs. The researchers would like to determine whether individual microRNA strands possess the antiviral properties sufficient for disabling viruses, or if combinations of different microRNAs are required. Future studies will also include testing immune responses for additional families of airborne viruses aside from those responsible for URIs.

"If we can learn how to manipulate the immune system into doing what it does best, the possibilities are endless," said Dr. Huang. "Identifying how it responds to temperature is just the first step."

Until then, the best way to avoid nasty colds, flu, and other URIs is to keep the immune system healthy during colder seasons. Masks worn over the mouth and nose not only protect from airborne pathogens but keep air inside the nose warm. And, if anything else, maintaining good hygiene, a healthy diet, and plenty of rest should help keep bothersome infections at bay.

Learn more about the Department of Otolaryngology–Head and Neck Surgery at Mass Eye and Ear

Refer a patient to Mass Eye and Ear/Mass General Brigham