During a malaria infection, countless Plasmodium parasites simultaneously destroy the red blood cells they’ve inhabited. This destruction causes a wave of fever and chills in the infected person that happens predictably every 24, 48, or 72 hours, depending upon which strain of the parasite is causing the infection.
For years, scientists have hypothesized that the host’s biological rhythms were responsible for the coordination and timing of the actions of Plasmodium. But in two studies published in Science today (May 14), researchers reveal that the parasites have their own inherent clock that both responds to the host and is capable of oscillating on its own.
“There’s been a longstanding question in the field as to why it is that malaria parasites are synchronous inside mammalian hosts. Is it because of the host or is it because of the parasite?” asks Audrey Odom John, a physician-scientist at Children’s Hospital of Philadelphia who did not participate in the work. “These are really synergistic studies that clearly address that question and definitively show that the parasite itself has an intrinsic clock, an intrinsic rhythm that is part of where the periodicity of the parasite cell cycle comes from.”
Filipa Rijo-Ferreira, a postdoc in Joseph Takahashi’s lab at UT Southwestern Medical Center, and her colleagues showed in 2017 that the parasite that causes human sleeping sickness had an internal clock. After that, she says, the characteristic rhythmic fevers seen in malaria made it obvious to look at the Plasmodium parasite for internal oscillations next. (Takahashi is a member of The Scientist’s editorial advisory board.)
In one of the new Science studies, Rijo-Ferreira and colleagues infected mice with P. chabaudi, which causes a mouse model of malaria. They found that neither putting the mice in constant darkness nor changing the animals’ feeding rhythms perturbed the parasite’s strong cell cycle and gene expression rhythms. When the researchers infected mice that were engineered to have a circadian clock that runs on a 26-hour, instead of a 24-hour, cycle, the parasites stretched their asexual life cycle to last 26 hours, rather than the typical 24, indicating that they are flexible and responsive to host oscillations.
At that point, the research team predicted that if the parasites did not have an intrinsic clock, they would quickly become desynchronized in a host without clear rhythms. But when they infected mice genetically engineered to lack a circadian clock with P. chabaudi, the parasites maintained a 24-hour rhythm of cell cycling and gene expression for between five and seven days, indicating that they do have a sense of internal timing. Because the parasites’ clocks fell out of synchrony eventually, the authors concluded that the parasites’ rhythms rely on their host for coordination.
“In the absence of these host cues, it loses its synchrony in the population. This suggests that the parasite has its own intrinsic rhythm, but the population is really synchronized by the host,” says Takahashi.
A group led by Steven Haase, a biologist at Duke University, showed in the other new Science study that four Plasmodium strains that cause malaria in people also exhibit intrinsic oscillations in gene expression and cell cycle activities when cultured in human blood. Although the parasites in culture lose synchrony faster than those in the mouse, the two-day window during which they can maintain their rhythms is similar to that of other culture systems that have been shown to have circadian clocks.
“This is a genuinely exciting and surprising result,” says Steve Kay, a biologist at the University of Southern California who did not participate in either study. “This oscillator . . . exhibits a lot of similarities to circadian oscillators and, to some degree, cell cycle oscillators in that it can maintain periodicity, and we see these massive gene expression programs that are regulated by whatever this oscillator is.” he says. At the same time, the plasmodium oscillator has evolved to require coordination with the circadian cycle of the host, and Plasmodium doesn’t have homologs for known circadian clock genes, which tend to be divergent across phylogeny anyway. It “appears to be not what we would understand as a canonical circadian clock. There’s a whole new clock to explore.”
“Taken together, these studies . . . reveal that parasites are themselves responsible for timing their replication, and that they require time-of-day information from the host to synchronize and schedule themselves,” Sarah Reece, a biologist at the University of Edinburgh who was not involved in the work, writes in an email to The Scientist. “I hope these groups will now be able to uncover the components of the parasite’s time-keeping mechanism.”
Looking into the mechanism is an obvious next step, as is investigating how the intrinsic clock in the parasite is talking to the host circadian clock, Haase says. “The idea is, if we can learn these mechanisms then we have targets potentially for new antimalarial treatments.”
F. Rijo-Ferreira et al., “The malaria parasite has an intrinsic clock,” Science, doi:10.1126/science.aba2658, 2020.
L.M. Smith et al., “An intrinsic oscillator drives the blood stage cycle of the malaria parasite Plasmodium falciparum,” Science, doi:10.1126/science.aba4357, 2020.