Exploring a genetic candidate for chloroquine resistance in the malaria parasite P. vivax

The emergence of chloroquine resistance threatens the efficacy of the recommended treatment for malaria infections caused by the parasite P. vivax. While the genes associated with chloroquine resistance in other malarial species have been well documented, knowledge of the mode of action in P. vivax is limited. Researchers from the Centre for Medical Parasitology in Denmark studied mutations in the multidrug resistance gene Pvmdr1 to explore the prevalence and extent of the mutations and examine whether they were driven by selection for drug resistance.

The researchers collected 267 samples from malaria endemic areas in Pakistan, Afghanistan, Sri Lanka, Nepal, Sudan, São Tomé and Ecuador. They isolated and amplified the section of DNA containing the Pvmdr1 gene and compared variations in the sequence. They found that variation was confined to three codons. Mutations in these codons were very common, with only 2.4% of samples wild-type at all three codons. The mutations appeared to have originated in multiple backgrounds by convergent evolution. Clear geographic differences in the prevalence of mutation combinations were observed, with district level analysis carried out in Sri Lanka showing evidence of local selection and geographic dispersal of mutations between local sites.

To further examine for a positive selection for drug resistance, the researchers looked at flanking microsatellite regions around the Pvmdr1 gene but found little evidence of a selective sweep for positive natural selection, such as in response to the chloroquine drug. This may reflect limited drug selection pressure but may also point to differences in resistance transmission and selection dynamics in the P. vivax species. High grade treatment failure has not yet been reported for P. vivax meaning that there is less likely to be selective drug pressure. In addition P. vivax reproduces before symptoms arise which further reduces the spread and selection pressure on resistance.

In conclusion this study finds that chloroquine resistance in P. vivax may be more complicated than previously described for other malaria species, with resistance emerging independently on multiple occasions. Further research is needed to illuminate the genomic level of change underpinning the spread of resistance. At a population level monitoring and research of chloroquine resistance as it emerges is vitally important to ensure that suitable treatment remains available for areas endemic for P. vivax malarial infections.

The research has been published in PLOS Neglected Tropical Diseases.

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