Cold exposure impairs extracellular vesicle mediated nasal anti-viral immunity

Published: December 6, 2022

The upper respiratory tract is one of the first sites of contact between the outside environment and inside the human body. When pathogens are inhaled, the upper respiratory tract triggers an array of immune responses to protect itself against these pathogens. The incidence of respiratory viral infections is highly affected by seasonal changes, but an answer to the crucial question of why people are more vulnerable to catching the common cold during the winter months and its underlying biological mechanisms remain understudied.

In a recent issue of The Journal of Allergy and Clinical Immunology (JACI), Huang et al. report a new virus-fighting immune mechanism inside the nose, which is mediated by extracellular vesicles (EVs) - small lipid enclosed particles that are naturally released from cells and is deficient in cold. They first evaluated the anti-viral activity of EVs in vitro using human nasal cells and live nasal mucosal tissues. They also identified several protective cargos that are carried by EVs to fight off respiratory viruses, including microRNAs (miRNAs) and surface receptor proteins. To test how colder temperatures affected this virus-fighting immune mechanism, they took healthy volunteers from a room temperature environment (23.3 °C) and exposed them to colder temperatures (4.4 °C), measured the temperature drop inside the nose, and applied this reduction in intranasal temperature to in vitro nasal cell and tissue cultures.

Viruses triggered an EV swarm response from nasal cells using the Toll-like receptor-3 (TLR3) signaling pathway, which is involved in activation of innate immune defense against the virus. EV swarms exhibited potent anti-viral activity against two rhinoviruses and a coronavirus that are typical of the common cold season. Upon EV release from cells, they delivered anti-viral miRNAs to uninfected host cells, protecting them from viruses. Another interesting anti-viral mechanism is that the EVs acted as decoys, carrying surface receptors that the virus would bind itself to instead of the uninfected host cells. This virus-fighting immune response mediated by nasal EVs was blunted by cold temperatures. Cold exposure induced a nearly 42% decrease in EV secretion with reduced anti-viral miRNA packaging and up to 77% loss of decoy receptors. This impaired immune response resulted in up a doubling of viral replication within infected nasal cells.

This investigation is of unique clinical relevance in that all cell culture data were directly validated in live human nasal mucosal tissues taken from fresh surgical specimens. Findings in this study thereby not only discover a new immune mechanism inside the nose that fights off viruses causing upper respiratory infections but also explain why people are more susceptible to colds in the winter season.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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