Seeing how the malaria can withstand fever’s warmth

Overview

• Post By : Kumar Jeetendra


• Source: Duke University


• Date: 06 Oct,2020

Even when a man suffering from malaria is burning up with fever and too ill to operate, the little 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 annually can withstand feverish temperatures that make their human hosts miserable. And today, 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 which springs into action to gird the parasite’s innards against heat shock.

Recognizing how the malaria parasite protects its cells from 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 investigators say.

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.

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.”

Kuan-Yi Lu, First Author

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

The human host’s body temperature may then rocket to 105 degrees or greater before dropping back down to normal two to six hours later, a roller coaster pattern that repeats itself every two to three times.

“It’s like moving from room temperature water to a spa,” 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 at the journal eLife, Lu spent hundreds of hours at parasites under the microscope, trying to determine 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 discovered that when temperatures rise, the parasites create more of a lipid molecule known as phosphatidylinositol 3-phosphate, or PI(3)P.

This substance accumulates in the outer wall of a very small sac inside the parasite’s cells called the food vacuole — the protist’s version of a gut.

With this lipid-protein increase, the team found that heat can make the food vacuole start to flow, 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 significant because they could help researchers make the most of current 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 along with other medications that decrease the parasite’s PI(3)P lipid levels and disrupt the food vacuole’s membrane — may be a method to re-sensitize resistant parasites, breaking down their defenses so the malaria treatments we already have are effective again.

The findings also suggest caution in giving malaria patients aspirin for fever if they are already taking artemisinin-based compounds, Derbyshire said. That’s because artemisinins kill malaria parasites by damaging their cell’s survival machines, including the machinery that produces PI(3)P. If artemisinins suppress PI(3)P levels, and thus 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 indicated.

Much remains to be learned, Derbyshire said. “There is more work to do to establish the mode of action. But you could imagine designing new combination therapies to try and extend the life span of artemisinin and extend its effectiveness,” Derbyshire said.