Malaria, an infectious disease spread by mosquitoes, has been quickly gaining resistance to treatments in Uganda due to genetic mutations in the parasites that cause the disease. In a paper published in Nature Medicine this August, a team of Brown researchers contributed to identifying a cluster of these mutations, which are associated with decreased susceptibility to several commonly used antimalarial drugs.
The research was conducted in collaboration with the University of California at San Francisco, the University of North Carolina at Chapel Hill and the Infectious Diseases Research Collaboration in Uganda. The researchers worked to sequence the DNA of malaria parasites to look for clues of how to address growing drug resistance.
“Malaria remains one of the most important infectious disease threats globally, especially in children,” said Associate Dean of Global Health Equity Adam Levine, who was not involved in the study.
Associate Professor of Pathology and Laboratory Medicine and of Translational Research Jeffrey Bailey, one of the study’s principal investigators, explained that this research “came about with colleagues in Uganda, who had really been at the forefront of trying to do field work to test for resistance and strains or parasites coming right out of patients.”
The researchers noticed that parasites were becoming less susceptible to first-line antimalarial pills containing lumefantrine and artemisinin, another principal investigator Melissa Conrad — a professor of molecular microbiology and immunology at Johns Hopkins University — wrote in an email to The Herald.
“We couldn’t fully explain the changes in susceptibilities or the amount of variation we were seeing with mutations known to impact … how parasites respond to these drugs,” Conrad wrote. “That made us think there had to be more mutations that (were) yet to be identified.”
The decreased susceptibility drove the team to investigate possible changes in the genome sequence that were associated with the resistance, Bailey explained. Eventually, this led the researchers to adopt “the whole genome sequencing approach,” said Karamoko Niaré, the paper’s first author and a researcher in Bailey’s lab.
Within the parasite genome, Conrad wrote, researchers found a conserved region carrying three mutations. This genetic feature was found at higher rates in “northern and eastern Uganda, suggesting rapid selection,” she added.
According to Bailey, researchers saw a phenomenon called selective sweep — which is when one mutation “gets passed on and spreads through the population” because it is so advantageous for survival — happening with those mutations.
“We sequenced those historical samples to actually see how this genetic variation has evolved over time in Uganda, so we realized that before the implementation of artemisinin-based combination therapies in Uganda, this genetic variant was not there,” Niaré said.
According to Conrad, next steps include using CRISPR to identify the “specific mutation” that contributes to this specific type of drug resistance.
“We are also working to better understand the distribution of these mutations across Africa,” she added.
Amrita Rajpal is a senior staff writer covering science and research.
