Why viruses spread so easily in cold weather

Previous studies by the current author have found that one of the components of the immune response against respiratory viruses involves the release of swarms of membrane-bound particles called extracellular vesicles (EVs) by cells that line the nasal cavity.

EVs are membrane-bound particles that can carry a cargo of DNA, RNA, and proteins and 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-like temperatures resulted in lower temperatures — 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, explaining the increased susceptibility to common colds in winter.

The study’s lead author, Dr. Benjamin Bleier, associate professor of otolaryngology at Harvard Medical School, told Medical News Today: “We found this drop significantly reduced this innate immune response in the nose, decreasing not only the quantity of extracellular vesicles that swarmed the virus but the quality of them. This reduced response can make the virus more able to both stick to and then infect the nasal cells, where they can then divide and cause the infection.”

“We feel these findings offer one of the first true mechanistic, biological explanations for why people are more likely to catch colds and other viruses that cause upper respiratory infections in cooler weather.”
— Dr. Benjamin Bleier

Previous studies have shown that upper respiratory infections, including the common cold and flu, are more common in colder seasons.

This has been attributed to the increase in transmission of upper respiratory 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 could blunt the immune response elicited by the upper respiratory tract to these viruses, resulting in increased 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 reported that rhinoviruses, the most common cause of upper respiratory infections, can replicate more efficiently at lower temperatures in the nasal cavity than at higher temperatures.

The study also reported infected cells that line the nasal cavity produced a more subdued immune response at 33 degrees Celsius than at 37 degrees Celsius.

However, the mechanisms linking changes in environmental factors with increased susceptibility to the common cold are not well understood.

In the present study, the researchers further examined how changes in temperature could modulate the immune response elicited by the upper airways.

The nasal cavity is lined with the nasal mucosa or mucous membrane that secretes mucus. The nasal mucosa is the first site of contact with inhaled respiratory microbes and plays a critical role in protecting against infection.

The nasal mucous membrane can physically prevent the entry of microbes as well as secrete molecules with antimicrobial properties in the mucus.

The nasal epithelial cells, which are a part of the mucous membrane, also express toll-like receptors (TLRs) on their surface, 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 microbial toxins or proteins and trigger an immune response by stimulating the production of immune proteins.

In earlier studies, the authors of the current research showed that activation of TLR4, a type of toll-like receptor activated by bacterial toxins, can stimulate the release of a swarm of EVs.

In their research, they found that the activation of toll-like receptors resulted in the release of EVs that triggered a defensive response against pathogenic bacteria.

These EVs can carry proteins that can bind and neutralize microbes, moreover, they can donate their cargo to neighboring or more distant cells to enhance the immune response.

The study authors first characterized the role of EVs produced upon the activation of TLRs in mediating an immune response against respiratory viruses.

They conducted these experiments using human nasal epithelial cells cultured in the 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), which is a substance that resembles viral RNA.

TLR3 stimulation increased the secretion of EVs by the nasal epithelial cells. The researchers then isolated and purified these TLR3-stimulated EVs and tested their antiviral activity against three common respiratory viruses — rhinoviruses RV-1B and RV-16, and the coronavirus CoV-OC43.

The researchers found that exposure to isolated TLR3-stimulated EVs suppressed the infection of cultured human nasal epithelial cells by these respiratory viruses.

By labeling the EVs with a fluorescent tag, the researchers found that isolated TLR3-stimulated EVs were internalized by other nasal epithelial cells that were not exposed to poly I:C.

In other words, the cargo carried by these EVs could reach uninfected cells.

The researchers found that the TLR3-stimulated EVs showed higher levels of six microRNAs than EVs from unstimulated cells.

Notably, one of the six miRNAs, miR-17, has been shown to suppress viral replication. Moreover, the downregulation of the miR-17 levels in EVs reduced the antiviral activity of TLR3-stimulated EVs against human nasal epithelial cells infected with any 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.

Previous studies have also shown that EVs can express cell surface receptors that are used by viruses to gain entry into the cell. The expressed receptors can act as decoys and reduce the number of virus particles that can later infect cells.

In the present study, the surface receptor proteins involved in the entry of rhinoviruses RV-1B and RV-16 were more abundant in the TLR3-stimulated EVs than in unstimulated vesicles. Moreover, incubation of the 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 findings suggest that the expression of these cell surface receptors by the EVs potentially prevented the virus from subsequently infecting other cells.

The researchers then examined the impact of cold ambient temperatures on this antiviral immune response mediated by EVs. They first used endoscopy to assess changes in temperature inside the nasal cavity of healthy individuals in response to cold temperatures typically observed during winter.

A drop in the ambient temperature from 23.3 degrees Celsius to 4.4 degrees Celsius was associated with a decline in the temperature inside the nasal cavity by about 5 degrees Celsius.

The researchers simulated this 5-degree Celsius drop in intranasal temperatures in the laboratory by culturing human nasal mucosal 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 mucosa tissue explants, which are pieces of nasal tissue instead of cells cultured in the laboratory, also showed a similar decline in EVs secretion at 32 degrees Celsius compared with 37 degrees Celsius.

Incubation of the 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 EV by nasal epithelial cells but also reduce the abundance of packaged antiviral miRNA and the expression of cell surface proteins by EVs.

These results could facilitate a better understanding of respiratory infections as well as other conditions.

Dr. Santosh Kumar, a professor at the University of Tennessee Health Science Center, told MNT that:

“The study shows a significant role of nasal epithelial extracellular vesicles (EVs) in the sensitivity to viral or other infections and perhaps a self-defense mechanism via TLR. In addition, the EVs’ biology via TLR may change based on the presence of seasonal infectious agents or allergens. This provides an adaptive biological role of nasal epithelial EVs. The findings may also be generalized to other EVs generated by other organs/tissues upon exposure to other agents.”