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Polymorphism of Antifolate Drug Resistance in Plasmodium vivax From Local Residents and Migrant Workers Returned From the China-Myanmar Border.

ABSTRACT: Drug-resistant Plasmodium vivax malaria impedes efforts to control, eliminate, and ultimately eradicate malaria in Southeast Asia. P. vivax resistance to antifolate drugs derives from point mutations in specific parasite genes, including the dihydropteroate synthase (pvdhps), dihydrofolate reductase (pvdhfr), and GTP cyclohydrolase I (pvgch1) genes. This study aims to investigate the prevalence and spread of drug resistance markers in P. vivax populating the China-Myanmar border. Blood samples were collected from symptomatic patients with acute P. vivax infection. Samples with single-clone P. vivax infections were sequenced for pvdhps and pvdhfr genes and genotyped for 6 flanking microsatellite markers. Copy number variation in the pvgch1 gene was also examined. Polymorphisms were observed in six different codons of the pvdhps gene (382, 383, 512, 549, 553, and 571) and six different codons of the pvdhfr gene (13, 57, 58, 61, 99, 117) in two study sites. The quadruple mutant haplotypes 57I/L/58R/61M/117T of pvdhfr gene were the most common (comprising 76% of cases in Myitsone and 43.7% of case in Laiza). The double mutant haplotype 383G/553G of pvdhps gene was also prevalent at each site (40.8% and 31%). Microsatellites flanking the pvdhfr gene differentiated clinical samples from wild type and quadruple mutant genotypes (F _ST= 0.259-0.3036), as would be expected for a locus undergoing positive selection. The lack of copy number variation of pvgch1 suggests that SP-resistant P. vivax may harbor alternative mechanisms to secure sufficient folate.

SUBMITTER: Zeng W

PROVIDER: S-EPMC8265503 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSexual stage surface antigens are potential targets of transmission-blocking vaccines (TBVs). The gametocyte and gamete surface antigen P230, a leading TBV candidate, is critical for red blood cell binding during exflagellation and subsequent oocyst development. Here, the genetic diversity of Pvs230 was studied in Plasmodium vivax parasite isolates from the China-Myanmar border (CMB) and central Myanmar.MethodsPlasmodium vivax isolates were collected in clinics from malaria-endemic areas of the CMB (143 samples) and Myanmar (23 samples). The interspecies variable part (IVP, nucleotides 1-807) and interspecies conserved part (ICP, 808-2862) of Pvs230 were amplified by PCR and sequenced. Molecular evolution studies were conducted to evaluate the genetic diversity, signature of selection, population differentiation, haplotype network, and population structure of the study parasite populations and publicly available Pvs230 sequences from six global P. vivax populations.ResultsLimited genetic diversity was observed for the CMB (π = 0.002) and Myanmar (π = 0.001) isolates. Most amino acid substitutions were located in the IVP and cysteine-rich domain of Pvs230. Evidence of positive selection was observed for IVP and purifying selection for ICP. Codon-based tests identified specific codons under natural selection in both IVP and ICP. The fixation index (FST) showed low genetic differentiation between East and Southeast Asian populations, with FST ranging from 0.018 to 0.119. The highest FST value (FST = 0.503) was detected between the Turkey and Papua New Guinea populations. A total of 92 haplotypes were identified in global isolates, with the major haplotypes 2 and 9 being the most abundant and circulating in East and Southeast Asia populations. Several detected non-synonymous substitutions were mapped in the predicted structure and B-cell epitopes of Pvs230.ConclusionsWe detected low levels of genetic diversity of Pvs230 in global P. vivax populations. Geographically specific haplotypes were identified for Pvs230. Some mutations are located within a potential B-cell epitope region and need to be considered in future TBV designs.

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Polymorphism of Antifolate Drug Resistance in Plasmodium vivax From Local Residents and Migrant Workers Returned From the China-Myanmar Border.

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