Genetics underpinning artemisinin resistance revealed

large mosquito

NDM researchers have led the largest genome-wide association study to date of the malaria parasite Plasmodium falciparum. The new study published in Nature Genetics unveils a complex genetic architecture that enables the parasite to develop resistance to our most effective antimalarial drug, artemisinin. The results could help to improve early detection of emerging artemisinin resistance.

The global research collaboration analysed 1612 samples from 15 locations in Southeast Asia and Africa and found 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work together with a set of background mutations in four other genes to support artemisinin resistance.

“We are at a pivotal point for malaria control. While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective,” said Professor Nick Day. “We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”

Researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar and Bangladesh, scientists found that the distribution of different kelch13 mutations are localised within relatively well-defined geographical areas.

Mutations in the kelch13 gene were present, yet rare, in Africa but weren't associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa where most malaria deaths occur.

There remain many unanswered questions. 'We don’t yet know the role of these background mutations,' says Dr Olivo Miotto, a first author and Senior Informatics Fellow at MORU and the Centre for Genomics and Global Health. 'Some may not affect drug resistance directly, but rather provide an environment where drug resistance mutations are tolerated. Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.'

“These data serve as a reminder of how crucial surveillance and elimination programmes are,” says Professor Dominic Kwiatkowski. “At present artemisinin resistance appears to be largely confined to Southeast Asia but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread."