Abstract
BackgroundThe malaria elimination plan of the Greater Mekong Subregion (GMS) is jeopardized by the increasing number of Plasmodium vivax infections and emergence of parasite strains with reduced susceptibility to the frontline drug treatment chloroquine/primaquine. This study aimed to determine the evolution of the P. vivax multidrug resistance 1 (Pvmdr1) gene in P. vivax parasites isolated from the China–Myanmar border area during the major phase of elimination.MethodsClinical isolates were collected from 275 P. vivax patients in 2008, 2012–2013 and 2015 in the China–Myanmar border area and from 55 patients in central China. Comparison was made with parasites from three border regions of Thailand.ResultsOverall, genetic diversity of the Pvmdr1 was relatively high in all border regions, and over the seven years in the China–Myanmar border, though slight temporal fluctuation was observed. Single nucleotide polymorphisms previously implicated in reduced chloroquine sensitivity were detected. In particular, M908L approached fixation in the China–Myanmar border area. The Y976F mutation sharply decreased from 18.5% in 2008 to 1.5% in 2012–2013 and disappeared in 2015, whereas F1076L steadily increased from 33.3% in 2008 to 77.8% in 2015. While neutrality tests suggested the action of purifying selection on the pvmdr1 gene, several likelihood-based algorithms detected positive as well as purifying selections operating on specific amino acids including M908L, T958M and F1076L. Fixation and selection of the nonsynonymous mutations are differently distributed across the three border regions and central China. Comparison with the global P. vivax populations clearly indicated clustering of haplotypes according to geographic locations. It is noteworthy that the temperate-zone parasites from central China were completely separated from the parasites from other parts of the GMS.ConclusionsThis study showed that P. vivax populations in the China–Myanmar border has experienced major changes in the Pvmdr1 residues proposed to be associated with chloroquine resistance, suggesting that drug selection may play an important role in the evolution of this gene in the parasite populations.
Highlights
The malaria elimination plan of the Greater Mekong Subregion (GMS) is jeopardized by the increasing number of Plasmodium vivax infections and emergence of parasite strains with reduced susceptibility to the frontline drug treatment chloroquine/primaquine
We focused on the genetic diversity of the P. vivax multidrug resistance 1 (Pvmdr1) gene in the vivaxendemic area along the China–Myanmar border, hoping to understand the evolution of the parasites amid the falling CQ treatment efficacy [35] and increased proportions of vivax malaria in most areas of the GMS [3]
Genetic diversity of the Pvmdr1 gene Mutations in the Pvmdr1 gene have been associated with CQ resistance in P. vivax in some endemic areas
Summary
The malaria elimination plan of the Greater Mekong Subregion (GMS) is jeopardized by the increasing number of Plasmodium vivax infections and emergence of parasite strains with reduced susceptibility to the frontline drug treatment chloroquine/primaquine. Most countries in Southeast Asia are making steady progress in reducing the malaria burden; the six countries in the Greater Mekong Subregion (GMS) have set their goals to eliminate malaria by 2030 [1, 3] This elimination plan is, challenged by the difficulties to eliminate P. vivax because of its several biological features such as very low blood parasitemia that is often missed by conventional detection methods, and formation of hypnozoites in the liver of an infected individual that are responsible for subsequent relapses [4]. Some studies failed to detect a link between the Pvmdr mutations and reduced CQ sensitivity, raising doubts on the suitability of the Pvmdr mutations as markers for CQ resistance [29, 30]
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