Malaria has plagued mankind for centuries, and traces of the parasite have even turned up in the archaeological remains of mummified Egyptian royalty. Despite our efforts to fight back with medicines such as chloroquine and artemisinin (ART), it seems the mosquito-borne parasite has a knack for staying one step ahead of us.
Today, the parasite that causes malaria (Plasmodium falciparum) has evolved to become resistant to ART after acquiring a series of protective mutations. These genetic adaptations were thought to protect the parasite at the early stages of its life cycle, leaving the late-stage parasite still susceptible to antimalarial drugs.
A team led by Laurent Rénia, a Senior Fellow and Principal Investigator at A*STAR Infectious Diseases Labs (ID Labs), challenged this prevailing belief by leading a study investigating the biological dynamics of late-stage, drug-resistant parasites. “The late stages might have some counter strategies that were overlooked with the usual ring-orientated treatment susceptibility study designs,” he explained.
In collaboration with researchers from the University of Malaya and the Shoklo Malaria Research Unit in Thailand, the researchers obtained clinical malaria isolates from Northwest Thailand. They studied these samples for the formation of malarial rosettes—flower-shaped formations made by P. falciparum by binding to human red blood cells to camouflage itself from the immune system.
Rénia and colleagues discovered that drug-resistant parasite isolates formed rosettes within an hour of exposure to the antimalarial, which was faster than their drug-sensitive counterparts. This accelerated rosette formation gave the resistant parasites a survival advantage, buying time for them to mature into the hardier ring stage.
The team also identified two gene deletions linked to this accelerated rosetting phenomenon, thereby highlighting how drug resistance in P. falciparum involves complex processes across its different developmental stages.
Rénia said that the results from the study could be applied to a lab-based test for ART resistance. “The speed of rosetting in response to drugs may also offer a simple and fast forecast of treatment susceptibility of the parasites to a drug of interest.”
As part of the effort to reduce the global death toll caused by malaria, Rénia and colleagues are now looking into next-generation treatments that chemically block the parasite’s ability to form rosettes. The team was recently awarded a patent for discovering a novel compound for use as an adjunct therapy for severe malaria.