We don’t really know, what we do know is that some cold causing viruses grow better at lower temperatures. Rhinoviruses, one of the most common causes of the common cold, display a temperature dependent growth pattern. They were shown to grow better at cooler temperatures (33°C – 35°C) (1,2) like that in the upper respiratory tract than at the core body temperature of 37°C. Scientists hit a wall when they looked for a reason for this by analyzing the viruses themselves. Entry of the virus inside the cell, for instance, was not affected at cooler temperatures (33°C- 35°C). The failure to find a convincing mechanism such as a temperature dependent viral enzyme or gene product was puzzling until recently, when scientists turned the table and started looking at the virus infected cell rather than the virus itself.
More about the study
A study published in the Proceedings of the National Academy of Science (PNAS) looks at cellular defense mechanisms and antiviral responses that come into play when Rhinoviruses infect cells (3).
The authors of this study compared the response to infection at the warmer body temperatures (37°C) and at cooler temperatures as found in the nasal cavity (33°C).
In what we think is the first step to understanding the role of the host (human) in this process, this study used a mouse adapted strain of the virus. They generated this strain by growing the virus for many generations in mouse cells. Subsequently the virus acquired mutations, adapted and was able to infect mouse airway cells. Foxman et al., isolated mouse airway epithelial cells and used the adapted strain to infect these cells in the laboratory. In order to test the temperature sensitivity, they carried out infection experiments at 33°C (cooler) and 37°C (warmer) temperatures. They observed the expected decrease in number of viral particles (titers*) starting from 7 hours after infection at 37°C but not at 33°C, confirming that temperature does impact viral numbers. The changes observed were in fact in the infected cells which showed a lower antiviral response to the virus at cooler temperature.
When a cell gets infected by a virus, it puts out a signal saying “I am infected” by secreting molecules such as interferons and this is critical for mounting an antiviral response (4). The study by Foxman et al., shows that cells infected at cooler temperatures have lower expression of molecules critical to the antiviral response. The authors artificially activated a defense pathway (The RLR pathway) which results in interferon production, and show that this pathway has a lower response at 33°C than at 37°C. In other words there is lower production of interferons, at cooler temperatures. Further, by genetically mutating either molecules of this pathway or a receptor of interferon in mouse airway cells, the authors find an increase in viral titers even at warmer temperature (37°C).
These data suggest the cells may be able to ward off a Rhinovirus infection at warmer temperatures (37°C) due to a robust antiviral response resulting in the production of interferons. In the nasal epithelium which is in constant contact with the outside air, the temperature of the cells is likely to be low enough for Rhinovirus to get away with a successful infection. Rhinoviruses of course are one of many agents that cause cold and it is not known if other cold viruses are similarly checked at higher temperatures. It is likely that they use a repertoire of counter strategies to the host defense response, some aspects of which may be temperature dependent. The experiments in this study have been conducted on mouse cells grown in the lab. It remains to be seen if this holds true within living animals and whether it can be extended to human- cold virus interactions.
An interview with Dr. Ellen Foxman
Q. How would you place this work in context of the unanswered questions in the field?
Question #1: Why do Rhinoviruses grow better at nasal cavity temperature than at lung temperature? It has been known since the 1960s that most Rhinovirus strains replicate poorly at body temperature (37°C) and better at slightly cooler temperatures (33 – 35°C) such as the temperatures found in the nasal cavity. However, the reason for this was not known. In our study, we observed that Rhinovirus infected cells fight back against infection more at 37°C than at 33°C—in other words, the immune response triggered by the virus within infected is more robust at 37°C, and this is an important mechanism suppressing growth of the virus at 37°C. b. Question #2: Does temperature affect the immune response to diverse pathogens, or just the immune response to Rhinovirus? We found that two cardinal signaling pathways involved in immune defense were more active at body temperature than at nasal temperature: RIGI like receptor signaling and Type I interferon receptor signaling. Since these pathways help defend us against in many viral different infections, our results raise the possibility that cool temperature also provides an advantage to viruses other than Rhinovirus. For example, many respiratory viruses cause colds more often than they cause lung infections; perhaps this is a reason why. That being said, it will be important to directly test other viruses, since viruses are tricky and many viruses have evolved ways to interfere with the immune responses we studied.
Q. How do you plan to take this study forward? What are the strengths and limitations of your model system?
The strength of our study was that we used a very well defined experimental system in which we could change one variable at a time to identify the immune system machinery needed to fight Rhinovirus within infected cells and to examine the effect of changing the temperature without changing anything else. Specifically, we used mouse primary airway cells grown in the laboratory. This way, we could compare cells from normal mice with cells from mice that differed by only one gene within the immune system. This allowed us to pinpoint which molecules within the immune system were important for defense against Rhinovirus, and which defenses were (or weren’t) affected by temperature. Also, by culturing cells in the lab, we were able to place them in incubators with controlled temperatures to clearly assess the effect of temperature without other confounding factors. b. Limitations/next steps: Although in general mice have been a good animal model for the human immune system, mice aren’t humans, and the next step in the study will be to examine in more detail how these mechanisms work within the human airway.
Q. Rhinoviruses are known to sometimes infect the lower respiratory tract (5) what do you think is going on there?
One possibility is that the immune mechanisms required to block Rhinovirus infection don’t work as well in people who tend to have lung symptoms with Rhinovirus infection—for example, people with asthma. In our study, we found that if we used mouse cells lacking the necessary immune system machinery to block Rhinovirus infection, the virus could grow quite well at 37°C. There is some evidence that in airway cells from people with asthma, this machinery may not function properly; if this is the case, this might be what permits the virus to thrive at the warmer temperatures of the lung.
Q. Do you think alternating the temperatures (for example in a real world scenario inhaling steam or hot water gargling versus eating an ice cream) impact the success of Rhinovirus infection? In other words you perform the entire infection at one temperature, are there shorter time windows within which a temperature change would positively impact disease outcomes (for example gargling every morning or drinking hot water after eating an ice cream?) ?
We did do some temperature shift experiments (see Figure S3 in the paper.) We found that the level of the immune response tracked with the temperature of the cells during the time window when the virus was actively replicating; the temperature before the infection didn’t matter much. I would speculate that some exposure of infected cells to warm temperature at any point when the virus is actively replicating might be beneficial.
Q. What kind of experiments would you need to conduct to suggest to people that using different methods to increase the temperature of the upper respiratory tract – like drinking hot water may help fight cold? Have they been done?
The best way to prove that an intervention works is to directly test it, as you are suggesting. In this case, the best experiment would be to expose a group of volunteers to a fixed dose of Rhinovirus, and then place half of them on a well defined hot water drinking program (perhaps the other half could drink only cold water. If hot water program were effective, you would expect to see fewer colds develop in the hot water group than in the other group. This is a difficult study to perform: ideally, you would want to test a group of people who are identical in every way (genetics, behavior, environment, history of exposure to infections, etc.) except for the hot water drinking. In reality, this is quite hard to do, since every person is different! However, it might be possible to see an effect by studying a large group of people, especially if hot water drinking had a big impact (rather than a small effect) on whether or not colds developed after exposure to Rhinovirus. These types of studies can be very informative, but also can be complicated to interpret due to the inability to control all of the variables that may affect the outcome you are measuring (in this case, development of cold symptoms.) b. I do not know of any study considered to be definitive on this subject. However, I did a literature search and found a number of studies that have looked at the effect of hot liquids or steam inhalation on common cold symptoms, and I did find a number of these. You can read a few of these to get a feeling for the strengths and limitations. For example: i. Sanu and Eccles, 2008: This study tested the effect of hot liquid drinking on cold and flu symptoms in subjects who were recruited when they already had symptoms—the pathogen causing the symptoms is unknown. ii. Singh and Singh, 2013, meta-analysis of multiple studies looking at steam inhalation and common cold symptoms.
Q. You have emphasized on cell autonomous response to viral infections, what about the other aspects of the immune response? Do you think they could also contribute to temperature sensitivity?
We only looked at the cell autonomous immune responses in this study, and these were solely responsible for the temperature dependent blockade of Rhinovirus in our experiments. In the body, where many cell types are present, the responses we examined (RIGI like receptor signaling and the Type I interferon response) can profoundly affect nearby and even distant cells through the action of secreted chemicals (cytokines). In this way, the phenomena we observed could also contribute to the temperature dependence of other immune responses; however, as yet we have no evidence for this.
1. “Factors affecting the growth of Rhinovirus 2 in suspension cultures of L132 cells“. J. Gen. Virol., 1970
2. “In vivo and in vitro synthesis of human rhinovirus type 2 ribonucleic acid.” Yin FH, Knight E Jr. J Virol, 1972
3. “Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells.” Ellen F. Foxman et al., PNAS, 2015
5. “The ABCs of Rhinoviruses, Wheezing, and Asthma.”James E. Gern J Virol, 2010