Researchers have uncovered rhythms in the malaria parasite’s gene activity levels that don’t rely on time cues from the host, but are instead coordinated from within the parasite itself.
When a person gets malaria, a rhythmic dance takes place inside their body. Successive broods of parasites multiplying in sync inside red blood cells, then bursting out in unison every few days, cause the disease’s telltale signs—cyclical fevers and chills.
The new study in Science shows that even when grown outside the body, malaria parasites can still keep a beat.
The findings indicate that the parasite that causes malaria has its own timekeeping machinery; an internal metronome that ticks of its own accord and causes thousands of parasite genes to ramp up and down at regular intervals.
“Malaria has all the molecular signatures of a clock,” says lead author Steven Haase, a professor of biology at Duke University.
Understanding how malaria’s clock works might help develop new weapons against a disease that kills a child every two minutes, and has proven increasingly resistant to existing drugs, Haase says.
Haase has spent years studying cell cycles in yeast to understand controls on the timing of events as one cell becomes two. But only recently has he turned to malaria. The work was prompted by a question that has vexed scientists: How do the parasites keep time?
Researchers have long known that all the malaria parasites within an infected person’s body—millions of them—move through their cell cycle at the same time. They invade red blood cells, proliferate, and erupt out in synchronous waves, releasing new parasites that invade other red blood cells, and the cycle starts anew. But whether the parasites were actively coordinating their own schedule or merely responding to the daily circadian rhythms of their human host was a mystery.
In the new study, the researchers grew four strains of the malaria parasite Plasmodium falciparum in human red blood cells in the lab, where they isolated the parasites from daily fluctuations in their host’s body temperature, melatonin levels. and other bodily rhythms.
Researchers 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.
The researchers note 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.
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 coauthor Francis Motta, assistant professor of mathematics at Florida Atlantic University.
A separate study of mice infected with malaria, also published in Science, supports the team’s findings. Circadian rhythms expert Joseph Takahashi, an HHMI investigator at the University of Texas Southwestern Medical Center, led that work.
While very little of malaria’s genome resembles clock genes found in other organisms, “it’s how the genes are arranged in a network that’s important,” Haase says.
Other biological clocks consists of a network of interconnected genes that are switched on until the proteins they produce start to build up. In a chemical feedback loop, the higher concentration of proteins then acts to shut down the genes that made them.
As a next step, the team is looking into whether there is any crosstalk between the malaria clock and the clock ticking inside the cells of the human immune system.
The thinking is that parasites that are able to anticipate when their host’s defenses are likely to be down can adjust the timing of their escape from red blood cells, possibly giving them an edge over more rhythmically challenged counterparts.
If we can figure out if and how the malaria parasite synchronizes the ticking of its clock with that of its host, Haase says, we might be able to disrupt those signals and help the human immune system better fight these invaders.
Support for this research came from the Defense Advanced Research Projects Agency, the National Institutes of Health, and the National Science Foundation.
Haase and coauthor John Harer are members of Mimetics, LLC. Harer is CEO of Geometric Data Analytics, Inc. Coauthors Tomas Gedeon and Bree Cummins are on the board of Kanto, Inc.
Source: Duke University