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Apr 02, 2023

Fighting Malaria Based on the Targeting of Biological Clocks

Plasmodium malariae protozoan inside red blood cells in the ring-form

Plasmodium malariae protozoan inside red blood cells in the ring-form trophozoite stage, computer illustration [Kateryna Kon/Science Photo Library/Getty Images]

Health officials warn that drug resistance could wipe out recent progress against malaria, particularly in Africa and Southeast Asia. Now, researchers looking for other ways to fight the mosquito-borne parasites that cause the disease have zeroed in on a potential new target: biological clocks.

In a new study, "The parasite intraerythrocytic cycle and human circadian cycle are coupled during malaria infection" published in PNAS, researchers analyzed gene activity in patients who showed up at medical facilities along the Thailand-Cambodia border, showing signs of a malaria infection in their blood.

The team found that malaria parasites somehow sync their molecular rhythms with the internal 24-hour clocks of their hosts, their respective genes rising and falling in perfect lockstep with each other over the course of a day, like two pendulum clocks with synchronized swings.

"During infections with the malaria parasites Plasmodium vivax, patients exhibit rhythmic fevers every 48 h. These fever cycles correspond with the time the parasites take to traverse the intraerythrocytic cycle (IEC). In other Plasmodium species that infect either humans or mice, the IEC is likely guided by a parasite-intrinsic clock [Rijo-Ferreiraet al., Science 368, 746–753 (2020); Smith et al., Science 368, 754–759 (2020)], suggesting that intrinsic clock mechanisms may be a fundamental feature of malaria parasites," the investigators wrote.

"Moreover, because Plasmodium cycle times are multiples of 24 h, the IECs may be coordinated with the host circadian clock(s). Such coordination could explain the synchronization of the parasite population in the host and enable alignment of IEC and circadian cycle phases.

"We utilized an ex vivo culture of whole blood from patients infected with P. vivax to examine the dynamics of the host circadian transcriptome and the parasite IEC transcriptome. Transcriptome dynamics revealed that the phases of the host circadian cycle and the parasite IEC are correlated across multiple patients, showing that the cycles are phase coupled. In mouse model systems, host–parasite cycle coupling appears to provide a selective advantage for the parasite.

"Thus, understanding how host and parasite cycles are coupled in humans could enable antimalarial therapies that disrupt this coupling."

The team of researchers at Duke University, Florida Atlantic University, and the Armed Forces Research Institute of Medical Sciences say the findings could pave the way to new anti-malarial drugs that throw malaria's internal clock out of step with its host, essentially "jet-lagging" the parasites.

"We have a reason to care about this," said senior author Steve Haase, PhD, professor of biology at Duke. "We’re on our last line of drugs, artemisinin-based combination therapies, and we’re already seeing resistance to those in southeast Asia. Exploring some new ideas for fighting malaria makes sense."

As a next step, the researchers are trying to figure out exactly how the parasite and human clocks "communicate" with each other so that their cycles line up.

"There have to be some molecular signals that they’re passing back and forth to each other," Haase said. "We don't know what they are, but if we can disrupt them, then we might have a shot at an intervention."

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