It is well recognized that we are more likely to suffer from upper respiratory illnesses during winter, but the biological mechanisms whereby the immune system responds differently in cold ambient conditions are unknown. A new study by researchers at Massachusetts Eye and Ear and Northeastern University has now identified a previously unknown immune response by cells inside the nose that fights off viruses responsible for upper respiratory infections. In addition, further testing has revealed that this protective response becomes inhibited in colder temperatures, making an infection more likely to occur.
“Conventionally, it was thought that cold and flu season occurred in cooler months because people are stuck indoors more, where airborne viruses could spread more easily,” said Benjamin S. Bleier, MD, FACS, director of Otolaryngology Translational Research at Mass Eye and Ear, and senior author of the study. “Our study, however, points to a biological root cause for the seasonal variation in upper respiratory viral infections we see each year, most recently demonstrated throughout the COVID-19 pandemic.”
The nose is on the front line of defense against airborne pathogens that enter the body from the outside environment. Microbes that are inhaled, or introduced into the front of the nose, by the hands for example, work their way backwards along the airway and can infect cells in the body and cause an upper respiratory infection. The airway protects itself against establishment of these pathogens, but the exact mechanism by which this happens is poorly understood.
A previous 2018 study, led by Dr. Bleier and Dr. Mansoor Amiji identified that the cells of the nasal epithelium initiate an innate immune response when bacteria are inhaled through the nose. Cells in the front of the nose detected the bacteria and respond by releasing billions of tiny, fluid-filled sacs called extracellular vesicles (or EVs) into the mucus to surround and attack the bacteria. Dr. Bleier compares the release of this EV swarm to “kicking a hornets’ nest.”
Further investigation showed that the EVs produce antibacterial proteins that migrate through the mucus from the front of the nose to the back of it, along the airway. The proteins bind to bacterial cells and neutralize them, and the presence of the proteins along the airway protects the cells from infection by bacteria before the microbes get too far into the body.
In the current study, the researchers tested whether the same immune response was also triggered against viral particles that can cause upper respiratory infections. They obtained samples of nasal tissue from healthy volunteers and also from people undergoing surgery, and tested the cells’ responses when exposed to viral particles from one strain of coronavirus and two strains of rhinoviruses that cause the common cold.
Their results, published in the Journal of Allergy and Clinical Immunology, showed that these viruses also triggered an EV swarm response from the nasal cells, in the same way that the bacterial pathogens had done. The researchers also discovered the virus-fighting mechanism by which the EVs act to reduce the effect of the viral particles: on their release from the nasal cells, the EVs act as decoys by offering the viral particles an alternative receptor on which to bind, rather than binding onto the nasal cells themselves.
“The more decoys, the more the EVs can mop up the viruses in the mucus before the viruses have a chance to bind to the nasal cells, which suppresses the infection,” explained Dr. Di Huang.
The researchers then investigated whether having a colder nose, as would be the situation in winter, had any effect on the way in which this nasal immunity mechanism worked. The internal temperature of the nose is highly dependent on the temperature of the outside air it inhales, and this can be significantly lower at times during winter. The researchers took healthy volunteers from a room temperature environment and exposed them to a temperature of 4.4° C (39.9° F) for 15 minutes, and found that the temperature inside the nose fell about 5° C.
They then applied this reduction in temperature to the nasal tissue samples kept in the laboratory, and found that the predicted immune response by the nasal cells was less significant. The quantity of EVs secreted by the nasal cells decreased by nearly 42 percent and the antiviral proteins in the EVs were also impaired.
“Combined, these findings provide a mechanistic explanation for the seasonal variation in upper respiratory infections,” said Dr. Huang.
The researchers plan to test whether this nasal immune response works with other pathogens, and whether it can be identified in live animal models or even in humans who are exposed to pathogens. They propose that therapeutic interventions could be developed to strengthen the nose’s immune response in order to prevent infection by microbes that cause respiratory diseases. For example, a drug therapy, such as a nasal spray, could be designed to increase the number of EVs in the nose or binding receptors within the vesicles.
“We’ve uncovered a new immune mechanism in the nose that is constantly being bombarded, and have shown what compromises this protection,” said Dr. Amiji. “The question now changes to, ‘How can we exploit this natural phenomenon and recreate a defensive mechanism in the nose and boost this protection, especially in colder months?’”
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