Malaria parasite has an inbuilt clock

The parasite that causes malaria has its own internal clock, according to two new US studies published in the journal Science.

In the first, a team led by Steven Haase from Duke University says its findings suggest the parasite has a timekeeping machinery – a metronome that causes thousands of parasite genes to ramp up and down at regular intervals.

Researchers have long known, Haase says, that the millions of malaria parasites within an infected person’s body move through their cell cycle at the same time. What has not been clear is whether they actively coordinate their own schedule or merely respond to the daily circadian rhythms of their human host.

In the new study, he and colleagues grew four strains of the malaria parasite Plasmodium falciparum in human red blood cells in the lab, where they were isolated from daily fluctuations in their host’s body temperature, melatonin levels and other bodily rhythms. 

The team extracted the parasites’ RNA every three hours for up to three days and looked at when each gene was activated and what its level of expression was. They noted that, even without clues from a host, all the parasites within a given strain kept in step. 

Roughly 90% of the genes they examined appear to be clock-controlled, rising and falling in a predictable fashion, and with a sequence that repeats itself, over and over. 

And analyses show that the malaria clock keeps time just as well as the biological clocks that control sleep cycles, metabolism and other circadian rhythms in humans and other animals, says co-author Francis Motta, from Florida Atlantic University.

In the second paper, researchers led by Joseph Takahashi from the University of Texas Southwestern Medical Centre, report similar findings based on experiments in mice.

“It’s as if the entire parasite is under this 24-hour program,” Takahashi says. “We think that if we can figure out what controls that program, we’d have a new target to try to inhibit the life cycle of the parasite.”

In the recent work, he and colleague Filipa Rijo-Ferreira demonstrated that the rhythm of the parasite Plasmodium chabaudi persists in constant darkness and regardless of host feeding, with 4000 of its roughly 5000 genes cycling in their levels of activity. 

They then showed that the parasite can shift its daily rhythm and that its rhythm persists even in mice genetically altered to have no rhythm of their own.

Haase and Takahashi say they discovered by chance that they were working on the same question using different parasite species, they coordinated to publish their findings together. 

There are currently no drugs that target the circadian clock, but the idea is gaining traction, Takahashi says. What’s more, “the efficacy of different drugs varies with time of day,” he says. 

For example, some cholesterol-lowering drugs are taken at the end of the day to better work with our circadian rhythms, as cholesterol is produced mainly at night.

In the case of malaria, Plasmodium parasites are already showing signs of resistance to existing drugs. The new study hopefully opens the door to “exploring whether the timing at which you give a drug can make it more effective,” Rijo-Ferreira says.