Second gene implicated in malaria parasite resistance to chloroquine

A groundbreaking study published in the journal Nature Microbiology reveals that the evolution of malaria parasites to resist the antimalarial drug chloroquine involves not just one, but two key genes. The research, conducted by an international team of scientists from institutions such as the Texas Biomedical Research Institute, the University of Notre Dame, and the Medical Research Council Unit The Gambia at the London School of Hygiene & Tropical Medicine, has significant implications for malaria control efforts worldwide.

Chloroquine was originally developed in the 1950s as a treatment for malaria and was widely used. However, drug resistance quickly emerged, first in Southeast Asia and then in Africa during the 1970s and ’80s. While chloroquine has since been replaced with other antimalarial drugs, the evolution of resistance remains a major challenge. In 2000, researchers identified a gene called pfcrt, known for its role in transporting chloroquine out of the parasites’ cells, thus rendering the drug ineffective.

The recent study focused on Plasmodium falciparum, the most deadly species of malaria parasites that infects humans. By analyzing over 600 genomes of P. falciparum collected in The Gambia from 1984 to 2014, the researchers discovered that mutations in a second gene, which encodes an amino acid transporter called AAT1, significantly increased in frequency over the 30-year period. These mutations closely correlated with the rise of pfcrt mutations, strongly suggesting the involvement of AAT1 in chloroquine resistance.

To confirm the role of AAT1 mutations in drug resistance, the research team conducted genetic crosses between chloroquine-sensitive and chloroquine-resistant parasites in the lab. They also used CRISPR gene-editing technology to replace the mutations in parasite genomes, observing the impact on drug resistance. The researchers also enlisted the help of collaborators to test the gene’s function in yeast and further validate the findings.

Additionally, the study revealed that AAT1 mutations associated with chloroquine resistance disappeared in Africa once chloroquine was no longer used, as expected. However, in Southeast Asia, where the drug is still in use, the mutations persist. This highlights the differences in drug resistance evolution between Africa and Asia and suggests that the specific mutations in the AAT1 gene contribute to these variations.

Interestingly, previous research conducted over a decade ago on malaria species infecting rodents also identified the involvement of the AAT1 gene in chloroquine resistance. This underscores the importance of collaboration and knowledge sharing among researchers studying different malaria species in both humans and rodents.

The study emphasizes the need for a holistic approach to combating drug resistance, not only in malaria but also in other pathogens. The researchers stress the importance of considering the interplay between different genes and molecules in the evolution of resistance. By examining whole genomes and populations, scientists can gain critical insights into the mechanisms underlying drug resistance and develop more effective strategies for treatment and surveillance.

Source: Texas Biomedical Research Institute

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