For centuries, the nature of a fever — and whether it's good or bad — has been hotly contested.
In ancient Greece, the physician Hippocrates thought that fever had useful qualities, and could cook an illness out of a patient. Later on, around the 18th century, many physicians regarded fever as a distinct illness, one that could actually cook the patient, and so should be treated.
These days, researchers understand that fever is part of the immune system's response to a pathogen, one that's shared by many animal species. And while there's accumulating evidence that fevers can help kick an infection, precisely how they can help remains mysterious.
"There's a cultural knowledge that there's this relationship between temperature and viruses, but at a molecular level, we're quite unsure how temperature might be impacting viruses," says Sam Wilson, a microbiologist at the University of Cambridge.
There are two main ideas, he says. The heat of a fever itself could be harming the virus, akin to Hippocrates' hypotheses. Alternatively, the heat is a means to an end, either stoking our immune system to work better, or simply a regrettable, but unavoidable byproduct of fighting off an infection.
"The fact that there weren't definitive answers to these questions piqued my interest," says Wilson. That interest led to a study, published Thursday in Science, that suggests — at least in mice — that elevated temperature alone is enough to fight off some viruses.
Reaching this conclusion was tricky, says Wilson, since it's very difficult to disentangle the effects of a fever itself from the immune response that usually comes with it. "The stars had to align," he says.
To put this question to the test, Wilson and his colleagues first needed a pathogen. They settled on bird flu, because birds run hotter than humans.
The influenza A viruses that infect birds target their guts, which are a few degrees warmer than the airways favored by human influenza viruses. "This means that bird flus are adapted to replicate at a higher temperature, a temperature equivalent to that of a human fever," says Wilson.
The researchers pinpointed a part of the bird flu genome that helps the virus thrive in this warm environment, called PB1. They then inserted this heat-tolerant snippet into a human flu virus. This gave them two nearly identical versions of influenza, a normal human one, and a heat-tolerant one.
Those two strains allowed the researchers to ask what impact this ability to replicate at different temperatures might have on disease. They needed an animal to test the question, and laboratory mice turned out to be ideally suited.
"It just so happens mice don't mount their own fever to an influenza infection," says Wilson.
So the team simulated one by housing some mice at slightly elevated temperatures. Then they exposed the mice to either the normal human influenza virus, or the heat-tolerant version.
Under normal laboratory temperatures, mice infected with both strains got sick.
But when the team turned up the heat, a key difference emerged. Mice infected with the heat-resistant strain got sick, but those infected with the normal strain seemed relatively unscathed, suggesting the heat itself helped fight off the flu.
"This study reinforces the idea that temperature alone is an important and effective," part of the body's attempt to respond to infection, says Daniel Barreda, a microbiologist at the University of Alberta who wasn't involved in the research. But he says the study doesn't rule out that fever also helps the immune system work better, which could be important for fighting off viruses that aren't as sensitive to temperature as influenza.
Joe Alcock, an emergency physician and researcher at the University of New Mexico, also praises the study. But he points out that we shouldn't assume fevers work the same way in humans as they do in mice.
Still, Alcock says the study adds to the growing body of evidence that fever evolved for a reason. As a physician trained by a health care system that's often quick to treat fevers, that gives him pause.
"We treat fevers as almost like a knee jerk reaction, giving medicines like acetaminophen or tylenol," he says. Of course, in many circumstances treating fever is appropriate, since those high temperatures can damage human cells, too. But he says it should raise questions about when we should reach for Tylenol or ibuprofen when we've got a viral cold.
"Is it possible that by taking Tylenol or ibuprofen for a viral infection, that I might be actually making it tougher for my body to get rid of the infection?" says Alcock. "That's as yet an unanswered question."
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