Mild fever helps clear infections faster, new study suggests

It may be better to let a mild fever run its course instead of automatically reaching for medication, new University of Alberta research suggests.

Researchers found that untreated moderate fever helped fish clear their bodies of infection rapidly, controlled inflammation and repaired damaged tissue. "We let nature do what nature does, and in this case it was very much a positive thing," says immunologist Daniel Barreda, lead author on the study and a joint professor in the Faculty of Agricultural, Life & Environmental Sciences and the Faculty of Science.

Moderate fever is self-resolving, meaning that the body can both induce it and shut it down naturally without medication, Barreda explains. The health advantages of natural fever to humans still have to be confirmed through research, but the researchers say because the mechanisms driving and sustaining fever are shared among animals, it is reasonable to expect similar benefits are going to happen in humans.

That suggests we should resist reaching for over-the-counter fever medications, also known as non-steroidal anti-inflammatory drugs, at the first signs of a mild temperature, he says. "They take away the discomfort felt with fever, but you're also likely giving away some of the benefits of this natural response."

The study helps shed light on the mechanisms that contribute to the benefits of moderate fever, which Barreda notes has been evolutionarily conserved across the animal kingdom for 550 million years. "Every animal examined has this biological response to infection."

For the study, fish were given a bacterial infection and their behaviour was then tracked and evaluated using machine learning. Outward symptoms were similar to those seen in humans with fever, including immobility, fatigue and malaise. These were then matched to important immune mechanisms inside the animals.

The research showed that natural fever offers an integrative response that not only activates defences against infection, but also helps control it.The researchers found that fever helped to clear the fish of infection in about seven days -- half the time it took for those animals not allowed to exert fever. Fever also helped to shut down inflammation and repair injured tissue.

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How malaria parasites withstand a fever's heat

 Even when a person suffering from malaria is burning up with fever and too sick to function, the tiny blood-eating parasites lurking inside them continue to flourish, relentlessly growing and multiplying as they gobble up the host's red blood cells.

The single-celled Plasmodium parasites that cause 200 million cases of malaria each year can withstand feverish temperatures that make their human hosts miserable. And now, a Duke University-led team is beginning to understand how they do it.

Assistant professor of chemistry Emily Derbyshire and colleagues have identified a lipid-protein combo that springs into action to gird the parasite's innards against heat shock.

Understanding how the malaria parasite protects its cells against heat stress and other onslaughts could lead to new ways to fight resistant strains, which have evolved ways to survive the drugs traditionally used to kill them, the researchers say.

Nearly half of the world's population is at risk of contracting malaria. The disease kills 400,000 people a year, most of them children.

Long before the cause of malaria was identified, the disease's harrowing fevers were well known. References to them have been found on 5,000-year-old clay tablets from ancient Mesopotamia. The Greek poet Homer wrote about their misery. Hippocrates too.

The Duke team, collaborating with professor of biological engineering Jacquin Niles at the Massachusetts Institute of Technology, wanted to know how the malaria parasites inside a person's body make it through these fevers unscathed.

When the parasites enter a person's bloodstream through the bite of an infected mosquito, the temperature around them jumps from the balmy mid-70s of the mosquito to 98.6 degrees in the human. The human host's body temperature can then rocket to 105 degrees or higher before dropping back down to normal two to six hours later, a roller coaster pattern that repeats itself every two to three days.

"It's like going from room temperature water to a hot tub," said first author Kuan-Yi Lu, who earned his Ph.D. in molecular genetics and microbiology in Derbyshire's lab at Duke.

For the paper, published Sept. 25 in the journal eLife, Lu spent hundreds of hours peering at parasites under the microscope, trying to figure out what happens inside them when temperatures seesaw.

To mimic malarial fever in the lab, the researchers placed malaria-infected red blood cells in an incubator heated to 104 degrees Fahrenheit for six hours before bringing them back down to normal body temperature, 98.6 degrees.

They found that when temperatures rise, the parasites produce more of a lipid molecule called phosphatidylinositol 3-phosphate, or PI(3)P.

This substance builds up in the outer wall of a tiny sac inside the parasite's cells called the food vacuole -- the protist's version of a gut. There, it recruits and binds to another molecule, a heat shock protein called Hsp70, and together they help shore up the food vacuole's outer walls.

Without this lipid-protein boost, the team found that heat can make the food vacuole start to leak, unleashing its acidic contents into the gel-like fluid that fills the cell and possibly even digesting the parasite from the inside.

The findings are important because they could help researchers make the most of existing malaria drugs.

Previous research has shown that malaria parasites with higher-than-normal PI(3)P levels are more resistant to artemisinins, the leading class of antimalarials. Since artemisinins were first introduced in the 1970s, partial resistance has been increasingly reported in parts of Southeast Asia, raising fears that we may be losing one of our best weapons against the disease.

But the Duke-led study raises the possibility that new combination therapies for malaria -- artemisinins combined with other drugs that reduce the parasite's PI(3)P lipid levels and disrupt the food vacuole's membrane -- could be a way to re-sensitize resistant parasites, breaking down their defenses so the malaria treatments we already have are effective again.

"If there is an alternative way to increase the permeability of the digestive vacuole, it could make the digestive vacuole more accessible to those drugs again," Lu said.

The findings also suggest caution in giving malaria patients ibuprofen for fever if they're already taking artemisinin-based compounds, Derbyshire said. That's because artemisinins kill malaria parasites by damaging their cell's survival machinery, including the machinery that makes PI(3)P. If artemisinins suppress PI(3)P levels, and thereby make malaria parasites more vulnerable to heat stress, then fever reducers could prolong the time it takes for artemisinin-based drugs to kill the parasites, as some reports have suggested.

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