Researchers from Mass Eye and Ear and Northeastern University have discovered a previously unidentified immune response inside the nose that fights viruses responsible for upper respiratory tract infections. Further testing revealed that this protective response is inhibited at colder temperatures, making infection more likely to occur.
New studypublished on December 6 in The Journal of Allergy and Clinical Immunologyoffers the first biological mechanism to explain why viruses like the common cold, flu and COVID-19 are more likely to peak during colder seasons, the authors say.
“Conventionally, cold and flu season was thought to occur in the colder months because people are more stuck indoors where airborne viruses could spread more easily,” said said Benjamin S. Bleier, MD, FACS, director of translational research in otolaryngology at Mass Eye and Ear. and lead author of the study. “Our study, however, points to a biological root cause for the seasonal variation in viral upper respiratory tract infections we see each year, most recently demonstrated throughout the COVID-19 pandemic.”
Front line defense in the nose
The nose is one of the first points of contact between the external environment and the interior of the body and, as such, a likely point of entry for disease-causing pathogens. Pathogens are inhaled or deposited directly (e.g. by hands) in the front of the nose where they travel up the airways and into the body infecting cells, which can lead to an upper respiratory tract infection. How the airways protect against these pathogens has long been poorly understood.
That is until a 2018 study by Dr. Bleier and Mansoor Amiji, Ph.D., professor emeritus of pharmaceutical sciences at Northeastern University, discovered an innate immune response triggered when bacteria are inhaled by the nose: Cells at the front of the nose detected the bacteria and then released billions of tiny, fluid-filled sacs called extracellular vesicles (or EVs, previously known as exosomes) into the mucus to surround and attack the bacteria . Dr Bleier compares the release of this swarm of electric vehicles to “kicking in a hornet’s nest”.
The 2018 study also showed that EVs transport protective antibacterial proteins through mucus from the front of the nose to the back along the airways, which then protects other cells from bacteria before they do not penetrate too far into the body.
For the new study, the researchers sought to determine whether this immune response was also triggered by viruses inhaled through the nose, which cause some of the most common upper respiratory tract infections.
Virus-fighting mechanism tested under various conditions
Led by study first author Di Huang, Ph.D., a researcher at Mass Eye and Ear and Northeastern, the researchers analyzed how cells and nasal tissue samples taken from the noses of patients undergoing surgery and healthy volunteers responded to three viruses: a single coronavirus and two rhinoviruses that cause the common cold.
They found that each virus triggered an EV swarm response from nasal cells, albeit using a different signaling pathway than that used to fight bacteria. The researchers also discovered a mechanism at play in the response against the viruses: when released, the EVs acted as decoys, carrying receptors to which the virus would bind instead of nasal cells.
“The more decoys, the more EVs can mop up viruses in the mucus before the viruses have a chance to bind to nasal cells, suppressing the infection,” Dr Huang said.
The researchers then tested how colder temperatures affected this response, which is particularly relevant in nasal immunity given that the internal temperature of the nose is highly dependent on the temperature of the outside air it inhales. They took healthy volunteers in a room temperature environment and exposed them to temperatures of 4.4°C (39.9°F) for 15 minutes and found that the temperature inside the nose dropped d ‘about 5°C. They then applied this temperature reduction to the nasal tissue. samples and observed a blunted immune response. The amount of EVs secreted by nasal cells decreased by almost 42%, and EV antiviral proteins were also altered.
“Combined, these results provide a mechanistic explanation for the seasonal variation in upper respiratory tract infections,” Dr. Huang said.
Future studies will aim to replicate the results with other pathogens. The studies could take the form of challenge studies, where an animal or human model is exposed to a virus and its nasal immune response is measured.
Based on their recent findings, researchers can also imagine ways in which therapeutics can induce and enhance the innate immune response of the nose. For example, drug therapy, such as a nasal spray, could be designed to increase the number of EVs in the nose or binding receptors in the vesicles.
“We discovered a new immune mechanism in the nose that is constantly bombarded, and showed what compromises this protection,” said Dr Amiji. “The question now turns into, ‘How can we harness this natural phenomenon and recreate a defense mechanism in the nose and enhance that protection, especially in the colder months?’ “”
In addition to Drs. Bleier, Amiji and Huang, co-authors of the study were Maie S. Taha, Ph.D., Angela L. Nocera, Ph.D., and Alan D. Workman, MD of Mass Eye and Ear. The study was supported by funding from Northeastern University and the National Eye Institute of the National Institutes of Health (P30EY003790).
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