Researchers have identified an “internal timekeeping mechanism” driving the parasite that causes malaria, overturning current scientific understanding of infection and raising the possibility of new future treatments.
Malaria is characterized by its cyclical patterns of fevers and chills. The disease is transmitted to humans through the bite of a mosquito infected with Plasmodium parasites, invading the human red blood cells and triggering fevers and other associated rhythmic symptoms that recur ever 24, 48, and 72 hours depending on the species of Plasmodium. It was previously believed that these cycles were influenced by the circadian rhythms of the human host, but researchers now report that the parasite’s internal clock allows for thousands of genes to ramp up and down at regular intervals. However, researchers now say that these pulses are the internal clockwork of the parasite as it proliferates and “erupts” in synchronous waves.
"Malaria has all the molecular signatures of a clock," said Duke biology professor Steven Haase, the lead author of the stud, in a press release.
These findings are the result of two studies now published in the journal Science, the first of which built on previous findings that suggested the parasite that causes sleeping sickness has its own circadian rhythm and is capable of shifting its host’s circadian clock, making some people sleep during the day instead of at night. To determine how this might play out in humans, researchers at the Howard Hughes Medical Institute infected mice with Plasmodium chabaudi and found that 4,000 of its 5,000 genes cycle in daily rhythmic activity to eventually genetically alter the rhythms of the mice to the point that they no longer have their own rhythm.
Translating these findings at the human scale, researchers at the Department of Mathematical Sciences at Florida Atlantic University extracted four strains of the malaria parasite Plasmodium falciparum taken from human red blood cells. These parasites were isolated from the daily fluctuations of their host’s body temperature, melatonin influence, and other rhythms that make up a human’s daily cycle. RNA was extracted from the parasites every three hours for up to three days to determine when each gene was active. Even without the hose, 90 percent of the parasites’ genes were controlled by this internal clock.
"Malaria and its causal parasite, the Plasmodium genus, are fundamentally rhythmic entities. Our study has shown that the parasite has molecular signatures common to known circadian and cell-cycle oscillators," said study co-author Francis Motta of the Department of Mathematical Sciences at Florida Atlantic University's Charles E. Schmidt College of Science. "Each of the four strains we examined has a unique period, indicating strain-intrinsic period control. We also demonstrate that parasites have low cell-to-cell variance in a cycle period, on par with a circadian oscillator."
These thousands of genes turning on and off in a rhythmic fashion likely influences the physiological processes and the reactions they elicit in their host.
"It's as if the entire parasite is under this 24-hour program," said Joseph Takahashi, a neuroscientist at the University of Texas Southwestern Medical Center, in a statement. "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."
Understanding how the parasite is influenced by time may reveal new targets for potential therapies in what the researchers describe as a “moon shot”. Currently, there are no drugs that target the circadian clock, which could be particularly helpful as some drugs are known to be more effective at different times of the day. Researchers hope to next explore whether there is any form of cross-communication between malaria’s internal clock and that of the human immune system.
