How malaria parasites evolved to avoid a key antimalarial drug has long been thought to involve only one key gene. Now, thanks to a combination of field and laboratory studies, an international research team has shown that a second key gene is also involved in malaria’s resistance to the drug chloroquine.
The result published this week in the journal Nature MicrobiologyIt has implications for the ongoing battle against malaria, which affects an estimated 247 million people and kills more than 619,000 annually – most of them young children.
“With the rise of drug-resistant pathogens, it is important to understand how treatments drive the evolution of parasites and how that evolution may differ in different parts of the world,” says Professor Timothy JC Anderson, PhD, of the Texas Biomedical Research Institute. Lead authors of the paper.
Chloroquine was developed to treat malaria in the 1950s and has been widely used. Drug resistance emerged within a few years, spreading first through Southeast Asia and then across Africa in the 1970s and 1980s. Chloroquine has been replaced by a series of other antimalarial drugs, but the development of resistance remains a challenge to parasite control. In 2000, researchers identified a gene, the chloroquine resistance transporter (pfcrt), that had evolved to help parasites move chloroquine out of a key area of their cells, rendering the drug ineffective.
“The resistance gene, pfcrt, is notorious,” says University of Notre Dame professor Michael Werdig, and one of the paper’s lead authors. “Finding that pfcrt is an accomplice to the crime should not be surprising – genes interact with each other as part of evolution all the time. But it is only with new tools and our integrated approach that we can finally identify the specific culprit.”
Six types of malaria parasites infect humans; Plasmodium falciparum is considered the deadliest. In this paper, researchers from the Gambia Medical Research Council Unit at the London School of Hygiene & Tropical Medicine and collaborators analyzed more than 600 P. genomes of the second gene encoding an amino acid transporter (AAT1) increased from 0% frequency in 1984 to 97% frequency in 2014.
“This is a very clear example of the process of natural selection – these mutations have been favored and passed on at a very high frequency in a very short period of time, which indicates that they provide a significant survival advantage,” says The Gambia Medical Research Council unit of the London School of Public Health and Tropical Medicine Professor Alfred Ambua-Ngwa, Ph.D., and one of the first authors. “Mutations in AAT1 closely reflect increased pfcrt mutations. Given this, it strongly suggests that AAT1 is involved in chloroquine resistance.”
Teams at Texas Biomed, the University of Notre Dame and the Seattle Children’s Research Institute teamed up to conduct an experimental evaluation of how mutations affect drug resistance. Specifically, the researchers performed genetic crosses between chloroquine-sensitive and chloroquine-resistant parasites, suggesting the involvement of AAT1 mutations. Using CRISPR gene-editing technology, the researchers replaced mutations in the genomes of parasites in the laboratory and observed their effect on drug resistance. The University of Nottingham collaborators tested the function of the gene in yeast, which also showed that mutations led to drug resistance. Collaborating institutes also included the Wellcome Sanger Institute, the Mahidol-Oxford Tropical Medicine Research Unit and University of Utah Health San Antonio.
“This project would not have been possible without the dedication of many collaborators in the US, Europe, Asia and Africa,” says Ashley Vaughan, PhD, principal investigator at the Seattle Children’s Research Institute and one of the authors of the papers. “We combined very diverse methodologies, all of which came to the same conclusion.”
But the team didn’t stop there. Additional malaria genome datasets showed that AAT1 mutations conferring resistance disappeared in Africa once chloroquine use there was discontinued, which would normally be expected. However, it is a completely different story in Southeast Asia where the mutations survive.
“Our analyzes showed that parasites from Africa and Asia carry different pfaat1 mutations, and our experimental data suggest that this may underlie the differences we observe in the development of drug resistance in Africa and Asia,” says Dr. Fridge.
Remarkably, researchers analyzing different types of malaria that affect rodents found that the same gene was implicated in chloroquine resistance more than a decade ago. “It shows me that malaria researchers and human rodents need to talk more,” says Dr. Anderson.
Professor David Conway, PhD, at the London School of Hygiene & Tropical Medicine, stresses that countering drug resistance – for malaria and other pathogens – requires a comprehensive approach to drug development and pathogen control. “We have to realize that different genes and molecules will work together to survive therapies,” he says. “This is why looking at whole genomes and entire populations is so critical.”
Alfred Amambua-Ngwa et al, Evolution of chloroquine resistance in Plasmodium falciparum is mediated by putative amino acid transporter AAT1, Nature Microbiology (2023). DOI: 10.1038/s41564-023-01377-z
the quote: Study Implicates Second Gene In Evolution of Resistance of Malaria Parasites to Chloroquine (2023, May 11) Retrieved May 11, 2023 from https://phys.org/news/2023-05-implicates-gene-malaria-parasite-resistance.html
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