Most organisms have a biological rhythm—and not the kind your uncle thinks he has when he starts dancing at weddings and family gatherings. These rhythms often control metabolic events at the cellular level and can be particularly important for parasites to complete their intricate lifecycles. No parasites, and few other organisms, are as deadly as malaria, so understanding its molecular clock could open up new treatment approaches.
Now, a team of investigators led by scientists at UT Southwestern has uncovered that the malaria parasite is driven by its own inherent clock. This discovery overturns decades of conventional wisdom about malaria, as the prevailing theory has been that the parasite takes its cues from its animal hosts. Findings from the new study were published recently in Science through an article titled, “The malaria parasite has an intrinsic clock.”
It’s long been known that malaria induces cyclical fevers, which occur every two to three days in human hosts, depending on the species of infecting organism. This is the result of all the parasites simultaneously bursting the red blood cells of the host they infect.
“It’s as if the entire parasite is under this 24-hour program,” noted senior study investigator Joseph Takahashi, PhD, professor and chair of neuroscience at UT Southwestern. “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.”
Circadian clocks, which control metabolism on a daily rhythm, are important in virtually all living things, from bacteria to plants and animals. But little is known about the role of daily rhythms in parasites, which also have to contend with their hosts’ clocks.
In malaria, Plasmodium parasites grow inside the host’s red blood cells and destroy them, triggering fevers and other symptoms. Doctors have long noticed that these fevers are rhythmic, recurring every 24, 48, or 72 hours depending on the species of Plasmodium. But scientists have assumed the parasite merely follows its host’s 24-hour rhythm.
Takahashi, who discovered the genetic basis for mammals’ circadian clocks in the 1990s, suspected that the parasite might set its own rhythm. He and postdoc Filipa Rijo-Ferreira had observed something similar in another kind of parasite.
Rijo-Ferreira and Takahashi discovered in 2017 that the parasite that causes sleeping sickness has its own circadian rhythm. In 2018, they reported that the parasite shifts its host’s circadian clock, making people sleep during the day instead of at night. The idea that parasites have internal clocks “just exploded my imagination,” Rijo-Ferreira stated. Until then, no one had reported such a timing mechanism in a parasite. After that, malaria, with its cycling fevers, seemed like the most promising place to look.
“We showed that parasite rhythms are flexible and lengthen to match the rhythms of hosts with long circadian periods,” the authors wrote. “We also show that malaria rhythms persist even when host food intake is evenly spread across 24 hours, suggesting that host feeding cues are not required for synchrony. Moreover, we find that the parasite population remains synchronous and rhythmic even in an arrhythmic clock mutant host. Thus, we propose that parasite rhythms are generated by the parasite, possibly to anticipate its circadian environment.”
The researchers conducted a series of experiments using mice and the malaria parasite that infects them, Plasmodium chabaudi. First, they demonstrated that the parasite’s rhythm persists in constant darkness and regardless of host feeding, with 4,000 of the parasite’s roughly 5,000 genes cycling in their levels of activity. Then they 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.
The researchers saw that of the 5,244 genes expressed by the blood stage of Plasmodium, more than 80% had the same cyclic patterns of expression in both lighting conditions. The activity of these genes peaked at the same time and with the same intensity in both groups, suggesting that the lighting cues that drive biological clocks in their mouse hosts weren’t affecting rhythms for the parasites.
To see if the clock in Plasmodium still ran about 24 hours, even if the clocks in their hosts do not, the researchers studied the parasite’s gene activity in mice with a genetic mutation that causes their own circadian rhythms to run about 26 hours instead of the usual 24. Tests showed that the protozoa seemed to slow their cell cycles to match those of their hosts, stretching them out to cover the 26-hour period. However, this correlation wasn’t perfect—Plasmodium‘s gene expression lagged behind, taking several days to catch up with its long-period host. These findings suggest that although the parasite seems to take cues from its host, it still ran on its own time.
“This was a very exciting result since it was our first hint that parasites aren’t just following the host but could be able to tell time,” said Rijo-Ferreira. “We were on the right path.”
Further tests suggest that rhythmic feeding times—another external cue that drives biological rhythms in animals—also weren’t required for cyclical gene activity in Plasmodium. Similarly, these cycles persisted even in mouse hosts with mutations that completely obliterated their biological rhythms. However, in this latter case, the parasite’s rhythms gradually became dysregulated over time. These findings suggest that although individual parasites appear to be driven by their own biological clocks, they seem to need an external cue from their hosts to synchronize. Mathematical models that the researchers constructed support this idea.
Takahashi noted that further research will be necessary to confirm the parasite’s clocklike behavior. A companion study published in the same May 15 issue of Science, led by a group at Duke University, provided supporting evidence in humans. Identifying the mechanism behind this phenomenon, he said, could lead to new targets to attack malaria, either by disrupting its rhythms or by finding ways to capitalize on them by discovering points in the cycle when Plasmodium may be particularly vulnerable.
“This could add a whole new dimension to therapeutic treatment for this often fatal disease,” concluded Takahashi.