Scientists Pinpoint Factors Contributing to Resistance to Key Malaria Drug

Clinic in Preah Vihear, Cambodia.

In two new studies, international research teams including NIAID scientists describe how certain genetic mutations make malaria-causing parasites resistant to artemisinin, a key drug for treating the disease. The findings are published in the Dec. 11, 2014, online issue of Science.

Plasmodium falciparum is the deadliest of the five species of malaria-causing parasites that infect people. Artemisinin, in combination with other drugs, is the first-line treatment for the disease. Over the past decade, use of artemisinin-based combination therapies has contributed to an estimated 30 percent decrease in malaria death rates worldwide.

However, the emergence and spread of artemisinin resistance in P. falciparum threatens this progress in malaria control and elimination. Researchers first detected artemisinin resistance in Cambodia, and it has now spread in Thailand, Vietnam, and Myanmar and is beginning to emerge in parts of Laos. Recently, NIAID researchers and collaborators identified a genetic marker of artemisinin resistance in P. falciparum—mutations in a gene called K13-propeller.

In the current studies, international teams including NIAID researchers from the laboratory of Rick Fairhurst, M.D., Ph.D., investigated whether K13-propeller mutations actually cause artemisinin resistance and, if so, by what mechanism.

Malaria patient provides a blood sample.

In one of the studies, researchers genetically modified P. falciparumcollected from malaria patients in Cambodia, as well as reference parasites from various geographical origins. When scientists removed K13-propeller mutations, parasites were 70 to 140 times more likely to die after artemisinin exposure. When they added mutations to the K13-propeller gene, parasites were up to 70 times more likely to survive this drug exposure. Certain K13-propeller mutations conferred higher levels of survival to parasites recently collected from Cambodia than to older reference parasites, suggesting that additional genetic factors may be contributing to artemisinin resistance.

In the second study, researchers analyzed more than 1,000 P. falciparumsamples from 13 malaria-endemic regions of Southeast Asia and Africa, some with no evidence of artemisinin resistance and others where resistance is well-established. Using parasite isolates taken directly from malaria patients, they found that artemisinin resistance was associated with slower progression of blood-stage parasite development and changes in a certain cellular response that may enable the parasites to better withstand the effects of the drug.

These studies provide direct evidence that K13-propeller mutations cause artemisinin resistance and offer insights into the molecular basis of resistance. Understanding the genetic factors and mechanisms underlying drug resistance promises to aid development of new strategies to counter the threat that artemisinin resistance poses to global malaria control and elimination.

The study authors suggest a global K13 sequencing effort to track the spread of artemisinin resistance and mitigate its impact on malaria treatment and control programs.