Monday, 23 February 2015

Are colds more common in the cold?

It’s a common held belief that when it’s cold, you get a cold. That is to say, an infection with symptoms such as a sore throat, runny nose, congestion, sneezes etc. But I’m sure everyone knows what a cold is, and being that it’s winter (in the Northern Hemisphere), many of you may currently have one. But are colds actually more common when it’s cold, and why? A recent study published in the journal Proceedings of the National Academy of Sciences (PNAS) has perhaps suggested a reason.

Firstly, some background to the common cold. The disease typically referred to as a ‘cold' can be caused by any of up to 200 different virus strains - it’s hardly surprising colds are so common. The major cause, and probably best known, are the Rhinoviruses, which account for 30-35% of common cold cases (there are an estimated 1 billion cases per year in the USA alone). Rhinovirus is the topic of the paper published in PNAS I’ll get to shortly.

So do we actually get more colds when we are cold? The evidence is pretty inconclusive. Influenza virus (which in mild infections could cause cold like symptoms) is well known to cause more disease in winter months and is probably best studied. Low temperature and humidity, as found in winter months, have been shown to enhance influenza spread in a guinea pig model. It is possible that viruses are more stable at lower temperatures, allowing them ot persist on surfaces for longer, boosting chance for spread. Furthremore, cold temperatues, generally, give more favourable conditions for spread of viral diseases that need close contact; people spend more time indoors, often together, during winter months. Any virus that spreads through coughs and sneezes will have much greater chance to transmit.

It makes sense that there may be an increase in the number of common cold cases when temperatures are lower, but biologically, why would this happen? The short answer is we don’t really know. But the work published in PNAS, has perhaps shed some light on why the common cold may be more prevalent when it's chilly. The work, fronted by Ellen Foxman in the lab of Akiko Iwasaki, initially demonstrated that Rhinovirus replicated better in cells at 33℃ than it did at core body temperature of 37℃, suggesting the virus had an advantaged at a lower temperature.

A drop of 4℃ isn’t huge, but it was clear that there was some benefit to the virus when cells were colder - either the virus could grow better, or something in the cells was different; the latter of these two options turned out to be the case. The group found that at 33℃, the cells infected with Rhinovirus had a markedly reduced interferon response (part of the innate immune system). Interferon is a protein secreted by cells when they become infected. The release of interferon from an infected cell essentially warns neighbouring cells that there is a virus, interferon is a 'danger signal.' Interferon can trigger events in the neighbouring cells that cause upregulation of around 300 different genes that help to protect the cells in the vicinity of an infection, these genes produce an antiviral state. Imagine there was a burglary on your street. The victims would find that they have been burgled and call the police, the police may then distribute flyers informing you, and your neighbours, that there are criminals in the area, making sure you lock your doors and shut your windows. The interferon response is similar, a cell detects it is infected (people notice they have been burgled), signalling events occur in the cell (phoning the police), interferon is produced and released to other cells (police distributing fliers), these cells then switch on genes to protect themselves (locking doors and shutting windows).

Having seen that Rhinovirus replicated better at 33℃, and that the cells had a reduced interferon response, with the two likely being linked, the group demonstrated that Rig-1-like receptors (RLRs) were responsible for the detection of viral infection. In the previous metaphor, RLRs could be considered the owners noticing they have been burgled who then phone the police (setting the whole thing in motion). This then allowed for work to look at what was different in the cell at 33℃ compared to 37℃, of which there were a few options: 1) there could be less stimulation of RLRs at 33℃, 2) the RLRs may have decreased function at 33℃, or 3) the interferon response in the neighbouring cells may be diminished at 33℃. To again keep with the metaphor, these three options could be considered as: 1) nothing major has been stolen so the owners are slow to realise, 2) the owners had their phones stolen, so it takes longer to contact the police, or 3) no-one reads the police flyers. Hopefully that’s all clear because all three were found to be the case.

At 33℃, RLRs are less able to signal that there is an infection. The cells are also less able to produce interferon and spread this message to neighbours who are are slower to respond to this danger signal. All in all, the cells are on a go-slow in terms of their response to infection. In the meantime, the virus replicates and moves on to infect new cells before these can prepare themselves - the virus has finished the race before the cells have started.

Rhinovirus (
To recap, Rhinovirus can replicate better in cells that are at 33℃ compared to 37℃, seemingly because at 33℃ cells are less able to detect, signal and respond to an infection. The final experiment to demonstrate this effect was to flip everything on its head. At 37℃ the virus doesn’t replicate as well as it does at 33℃, presumably because there is better detection, signalling and response to the infection. To directly show that this enhanced response causes lower viral replication at 37℃, the group used cells that lack the signalling pathway that is induced following RLR detection of infection (there is no way to contact the police and tell them of the burglary). As you might expect, these cells supported much higher levels of viral replication than normal cells at 37℃, and even had replication that matched that seen at 33℃ - showing the importance of the IFN response in controlling infection at 37℃, compared to 33℃.

In the case of Rhinovirus, it seems that infection may be increased in the cold. The lower temperature doesn’t seem to particularly impact the virus, but instead impacts the innate immune response of the infected cells. Interferon is important for the control of all viral infections, so the fact that this response is attenuated at a lower temperature suggests that areas of the body naturally at lower temperature, and exposed to a cold atmosphere, such as the nasal cavity and upper airways, may be more susceptible to viral infection - perhaps explaining why so many viruses can cause common colds.

A graphic demonstration of a sneeze
It seems that Rhinovirus is capable of taking advantage of the lower temperature found in the upper airways, but what is interesting is why there hasn’t been any evolution of these cells to protect themselves from infection. Infections of the nasal cavities and upper respiratory tract don’t cause enough of a selective pressure for anything to change, it would seem. Getting a cold is rarely life threatening, if the virus were to spread deeper into the lungs where it could cause more damage, it would be hypothesised that these warmer cells would respond properly and wipe out the virus. Not only may colds be more common when it's cold, they may also be of little concern to our survival (let’s face it, how bad do colds really ever get).

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