New research explains the mechanism behind why we’re more prone to catching a cold or the flu in the winter. Fall and winter are associated with a higher incidence of upper respiratory tract infections, such as colds and flu, due to increased transmission of respiratory viruses. Although cooler temperatures and low humidity are associated with increased susceptibility to respiratory viruses, the biological mechanisms underlying this relationship are not understood.

A recent study showed that cold temperatures lead to a decreased immune response to viruses triggered by cells in the nasal cavity, which is why people are more susceptible to upper respiratory tract infections in cold weather. Scientists have attempted to explain the biological mechanisms underlying the increased incidence of colds and flu in winter. A study published in the Journal of Allergy and Clinical Immunology describes a mechanism in the nose that may explain the increased susceptibility to upper respiratory tract infections in winter.

The nose: A gateway for viruses?

Previous studies have revealed that one component of the immune response against respiratory viruses involves the release of swarms of membrane-bound particles, called extracellular vesicles (EVs), from the cells that line the nasal cavity. EVs are membrane-bound particles that can carry DNA, RNA, and protein cargo. They are released by most cell types and help produce an antiviral response. MiRNAs, a type of RNA, do not code for proteins but can regulate the expression of target genes.

In the nose, EVs can prevent viruses from binding to uninfected cells or transferring their cargo to uninfected cells and modulating their immune response. In the current study, winter temperatures caused temperatures to drop from 37 degrees Celsius to 32 degrees Celsius in the nasal cavity, which weakened this immune response. Specifically, this 5 degree drop in temperature inside the nasal cavity attenuated the release of EVs and the antiviral response mediated by these EVs, which explains the increased susceptibility to common colds in winter.

The study’s lead author, Dr Benjamin Bleier, of Harvard Medical School, explains: “We found that this drop significantly reduced this innate immune response in the nose, not only decreasing the amount of extracellular vesicles that were swarming the viruses, but also their quality. This reduced response can make the virus more able to stick to and infect nasal cells, where it can then divide and cause infection. »

These findings offer one of the first true mechanistic and biological explanations for why people are more susceptible to catching colds and other viruses that cause upper respiratory tract infections in cool weather.

Cooler temperatures and immune response

Previous studies have already shown that upper respiratory tract infections, including colds and flu, are more common during cold seasons. This phenomenon has been attributed to increased transmission of upper respiratory tract viruses due to changes in temperature and humidity and human behavior, such as spending more time indoors. However, more recent studies suggest that cold temperatures may dull the immune response triggered by the upper respiratory tract against these viruses, leading to greater susceptibility to infections.

Due to its proximity to the external environment, the nasal cavity is more sensitive to changes in ambient temperature than the rest of the body, including the lungs. A previous study indicated that rhinoviruses, the most common cause of upper respiratory tract infections, can replicate more effectively at lower temperatures in the nasal cavity than at higher temperatures.
The study also found that infected cells lining the nasal cavity produce a milder immune response at 33 degrees Celsius than at 37 degrees Celsius. However, the mechanisms that link changes in environmental factors to increased susceptibility to colds are not well understood. In the current study, the researchers investigated how changes in temperature could modulate the immune response triggered by the upper respiratory tract.

Role of extracellular vesicles

The nasal cavity is lined with the nasal mucosa or mucous membrane which secretes mucus. The nasal mucosa is the first site of contact with inhaled respiratory microbes and plays an essential role in protecting against infection. The nasal mucosa can physically prevent the entry of microbes and secrete molecules with antimicrobial properties into the mucus. Nasal epithelial cells, which are part of the mucosa, also express on their surface Toll-like receptors (TLRs), which can activate the innate immune response.

The innate immune response is the first line of defense against pathogens and is non-specific. TLRs can recognize structural patterns in toxins or microbial proteins and trigger an immune response by stimulating the production of immune proteins. In previous studies, the authors of the present research have shown that activation of TLR4, a type of toll-like receptor activated by bacterial toxins, can stimulate the release of an EV swarm.

In their research, they found that activation of toll-like receptors results in the release of EVs that trigger a defensive response against pathogenic bacteria. These EVs can carry proteins capable of binding to microbes and neutralizing them. In addition, they can transmit their cargo to neighboring or more distant cells to strengthen the immune response.

Antiviral effects

The study authors first characterized the role of EVs produced during TLR activation in mediating an immune response against respiratory viruses. They conducted these experiments using human nasal epithelial cells cultured in laboratory. To examine whether EVs are released in response to respiratory viruses, the researchers stimulated TLR3, a toll-like receptor that is specifically activated by viral RNA. They stimulated TLR3 using polyinosinic:polycytidylic acid (poly I:C), a substance that resembles viral RNA.

Stimulation of TLR3 increased VE secretion from nasal epithelial cells. The researchers then isolated and purified these TLR3-stimulated EVs and tested their antiviral activity against three common respiratory viruses – the rhinoviruses RV-1B and RV-16, and the coronavirus CoV-OC43. The researchers found that exposure to isolated TLR3-stimulated EVs suppressed infection of cultured human nasal epithelial cells with these respiratory viruses.

Antimicrobial cargo

By labeling the EVs with a fluorescent tag, the researchers found that the isolated TLR3-stimulated EVs were internalized by other nasal epithelial cells that had not been exposed to poly I:C. In other words, the cargo carried by the isolated EVs was antimicrobial cargo.

In other words, the cargo carried by these EVs could reach uninfected cells. The researchers found that EVs stimulated by TLR3 had higher levels of six microRNAs than EVs from unstimulated cells. In particular, one of these six microRNAs, miR-17, has been shown to suppress viral replication. Furthermore, downregulation of miR-17 levels in EVs reduced the antiviral activity of TLR3-stimulated EVs against human nasal epithelial cells infected with one of the three common cold viruses. This shows that the miRNA cargo carried by TLR3-stimulated EVs was transferred to other cells, where it helped generate an antiviral response.

Surface receivers

Previous studies have also shown that EVs can express cell surface receptors that are used by viruses to enter the cell. Expressed receptors can act as decoys and reduce the number of virus particles that can then infect cells.

In the present study, surface receptor proteins involved in rhinovirus RV-1B and RV-16 entry were more abundant in TLR3-stimulated EVs than in unstimulated vesicles. Moreover, incubation of TLR3-stimulated EVs with RV-1B and RV-16 reduced the ability of these viruses to infect human nasal epithelial cells. The researchers also found that these respiratory viruses directly interacted with cell surface receptors expressed by TLR3-stimulated EVs. These results suggest that expression of these cell surface receptors by EVs potentially prevented the virus from subsequently infecting other cells.

Impact of cold ambient temperatures

The researchers then examined the impact of cold ambient temperatures on this EV-mediated antiviral immune response. They first used endoscopy to assess temperature changes inside the nasal cavity of healthy individuals in response to cold temperatures typically seen in winter. A drop in ambient temperature from 23.3 degrees Celsius to 4.4 degrees Celsius was associated with a drop in temperature inside the nasal cavity of about 5 degrees Celsius.

The researchers simulated this 5 degree Celsius drop in intranasal temperature in the lab by culturing human nasal mucosa cells at 32 degrees Celsius instead of 37 degrees Celsius.
Lowering the temperature reduced the release of EVs in response to TLR3 stimulation. Human nasal mucosal tissue explants, which are pieces of nasal tissue and not lab-grown cells, also showed a similar drop in EV secretion at 32 degrees Celsius compared to 37 degrees Celsius.

Incubation of nasal epithelial cells at 32 degrees Celsius also reduced the abundance of miR-17 in EVs released after TLR-3 stimulation. Moreover, lowering the temperature reduced the expression of surface receptor proteins on TLR3-stimulated EVs that could serve as decoys. Thus, exposure to cooler ambient temperatures may attenuate not only the release of TLR3-stimulated EVs from nasal epithelial cells but also reduce the abundance of packaged antiviral miRNAs and the expression of cell surface proteins by EVs. .

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