Red-Hot Coverage for Study: “Cold Noses Cause Colds"

Colds can come from cold noses, according to a high-profile study in Proceedings of the National Academy of Sciences (PNAS).

More work is needed, many immunologists told Bioscience Technology and other media outlets in recent days. Still, the media blanketed news websites with headlines like “Cold Coddles Colds” and “Scientists Find out Why Your Granny was Right.”

The bottom line is that vindication may indeed be Granny’s. We probably all should bundle right up to our noses—and beyond—all winter.

“There were roadblocks everywhere” in the course of the research, senior author and Yale University immunobiologist Akiko Iwasaki told Bioscience Technology. But her crew was finally able to show that a lower temp in the nose indeed “impairs innate sensing and signaling, resulting in a condition that allows the [cold] rhinovirus to replicate.”

In mice, that is.

The basic finding

The basic finding of the Yale group was that the most frequent virus causing the common cold, the rhinovirus, can propagate better in the chill of the nose than at most core body temperatures. It is common knowledge this rhinovirus propagates more readily in the nose than in warmer lungs. But earlier work has focused on how body temperature influences the virus, not how the immune system influences it.

To nail the link between temperature and immunity, Iwasaki and a team including Yale post-doc Ellen Foxman examined cells from mouse airways. They compared the immune response to  rhinovirus when cells were kept at 37°C (core body temperature) and at 33°C.

The innate immune response to the rhinovirus was hampered at the lower nasal temperature.

The team also found evidence that the differing temps impacted immune cells directly. They saw rhinovirus proliferation in airway cells from mice with certain genetic deficiencies in immune system sensors that detect virus. These deficiencies let the virus reproduce at higher temps. The host’s immune response to the cold virus, the team concluded, matters most. 

The team believes the study may apply to humans—20 percent of whom are hosting a rhinovirus in their noses at any given time. The researchers also hope to find a similar link between temperature, immunity and asthma.

Answer: An “astounding yes!”

The work was not easy, Iwasaki told Bioscience Technology. “First, the rhinovirus does not replicate in mouse cells,” she said. Foxman had to generate virus that can adapt to mouse cells and replicate. “This took over 27 passages.”

Then she learned how to collect and grow primary mouse airway cells. “We had to figure out what innate sensors were responsible for generating type I IFN (interferon) response to rhinovirus,” she said. But finally, “we were able to test our hypothesis that rhinovirus replicates better at the cooler temperature due to impaired immune response. The answer was an astounding yes!” 

The group next plans to ascertain whether “similar mechanisms operate in human airway cells, and what we can do to block this virus replication given the impaired immune response at the cooler temperature,” she said. 

Some reservations

Some immunologists have reservations. Vincent Racaniello, a Columbia University virologist, told Bioscience Technology the work is based on the idea that “human rhinoviruses (HRVs) replicate better at lower temperatures. Hence, this could explain why they cause upper respiratory tract infections.”

But, Racaniello said, “much of the lower respiratory tract is also cooler (33°C to 35°C) than core temperature (37°C). These are certainly permissive for HRV replication, and it has been shown that HRVs replicate in the lower tract of humans inoculated with HRV.” Also, some HRVs cause “serious lower respiratory tract disease. The idea that HRVs are limited to common colds is simplistic,” he said.

Another problem, Racaniello said is that there are more than 150 different HRVs “and no one has determined if they all replicate better at low temperatures.” Racaniello continued, “In my lab, we routinely grow HRVs at 37°C and find no difference at 33°C. I suspect the idea that all HRVs grow better at low temperatures is simply wrong.”

Finally, he said, the work was done in mouse cell cultures.  “There is no reason to believe their results would also apply in humans. There are no really good animal models for studying HRV infection, so we can’t determine what controls the pattern of disease….The idea that temperature determines HRV disease is simplistic. The real question is, ‘Why do many rhinoviruses cause an upper tract disease, even though the virus can replicate lower in the tract?’”

Response

Iwasaki agrees with many of Racaniello’s points, most of which, she says, are addressed in the study. “We agree completely HRV is not just a common cold virus. We discussed at length the importance of HRV in childhood asthma exacerbation, and that is thought to be caused by HRV replicating in the lower lung. This makes our study of broader interest.”

Her team also agrees “not all HRV genotypes replicate well at the lower temperature,” if the majority do, she said. “We discussed the fact that one type of HRV, HRV C, replicates in the lower lung (37°C) in our study. Based on our findings, it would be interesting to figure out whether those HRV that replicate well in the warmer temperature may have specific mechanisms to antagonize the RLRs or IFNR signaling.” 

Iwasaki said the study made it clear it was limited to mouse airway culture and must be repeated in human. Her study also showed a key finding in HRV disease, “that lower temperature promotes replication of HRV, and that this is, in large part, due to the impaired innate immune response to the virus.”

Other Racaniello points will be addressed later, she said. “We believe there is a gradient of immune regulation along the temperature gradient of the respiratory tract. Our data might shed light on why the virus might cause upper tract disease in most humans. This may very well have to do with the extent of virus replication (and induction of host counter-response like mucus secretion) in the upper airway, compared to lower airway, due to the gradient of immune competence along the respiratory tract.”

On the flip side, Iwasaki said, “in asthma patients who harbor HRV in lower lung, virus replication in the warmer temperature suggests the patients are less able to trigger antiviral defense signals. A compensatory immune response engaged against the HRV may be the culprit of asthma attack. Our study provides the basis to tackle future questions of HRV disease.”

Other reservations

Other reservations came from Ron Eccles, director of the Cardiff University Common Cold Centre. The paper, he told Bioscience Technology, assumes the normal body temperature of a mouse is 37°C and the normal nasal temperature is 33°C. “This may be true for humans, but is not the case for mice. Body temperature in mice ranges from 34°C to 39°C,” he said.

Also, nasal temp in mice is unknown and difficult to measure “without damaging the nose and disturbing the temperature. I doubt if it is 33°C, as the normal respiratory rate in a mouse is 163 a minute, compared to around 12 a minute in man, and the rate of ventilation could influence the temperature,” he said. 

Then there is the fact that mice have more complex nasal structures. “I would expect the deeper parts of the nose to always be close to body temperature,” Eccles said. He added that mice are not normally infected with rhinovirus, possessing very different viral receptors than humans; and that the study’s airway cells may not be compatible with either mouse or human nasal epithelial cells.

Finally, Eccles said, “if the nose is normally 33°C, it would have been better to cool cells below this, rather than compare at 37°C. In my 2002 hypothesis paper I put this idea forward. I also speculated that when one side of the nose gets blocked during a cold it raises the nasal temp to 37°C. This could be part of respiratory defense, and could inhibit viral replication.”

In general, he said, “The investigation demonstrates that raising the temperature in an immune cell raises its metabolic activity, and this is nothing new.”

Iwasaki responded that, as her team conducted the entire study in tissue culture on airway cells isolated from mouse, “any concerns regarding the natural nasal temperature of mouse are lifted, because the temperature for experiments were set precisely by the incubators.”

She said the team is not claiming their work is relevant to humans. She has stated that more studies are needed to determine this “in every media interview.” 

Furthermore, Iwasaki said, “our study included a control showing that impaired immune response does not reflect metabolic activity of the cells in general. Other cell types we have tested (plasmacytoid dendritic cells) that rely on different viral sensors respond identically to rhinovirus at both temperatures.” 

Iwasaki concluded, “Our study shows the fundamental discovery that temperature changes the way the immune system responds to rhinovirus.”