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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 | 2021

REPOSITORIES: biostudies-literature

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

Zeng Weilin W Wang Siqi S Feng Shi S Zhong Daibin D Hu Yue Y Bai Yao Y Ruan Yonghua Y Si Yu Y Zhao Hui H Yang Qi Q Li Xinxin X Chen Xi X Zhang Yanmei Y Li Cuiying C Xiang Zheng Z Wu Yanrui Y Chen Fang F Su Pincan P Rosenthal Benjamin M BM Yang Zhaoqing Z

Frontiers in cellular and infection microbiology 20210624

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 ...[more]

PMID: 34249776

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Project description:BackgroundPlasmodium vivax remains the predominant species at the China-Myanmar border, imposing a major challenge to the recent gains in regional malaria elimination. To closely supervise the emerging of drug resistance in this area, we surveyed the variations in genes potentially correlated with drug resistance in P. vivax parasite and the possible drug selection with time.MethodsA total of 235 P. vivax samples were collected from patients suffering uncomplicated malaria at Yingjiang, Tengchong, and Longling counties, and Nabang port in China, Yunnan province, and Laiza sub-township in Myanmar, from 2008 to 2017. Five potential drug resistance genes were amplified utilizing nested-PCR and analyzed, including pvdhfr, pvdhps, pvmdr1, pvcrt-o, and pvk12. The Pearson's Chi-squared test or Fisher's exact test were applied to determine the statistical frequency differences of mutations between categorical data.ResultsThe pvdhfr F57I/L, S58R, T61M and S117T/N presented in 40.6%, 56.7%, 40.1%, and 56.0% of the sequenced P. vivax isolates, and these mutations significantly decreased with years. The haplotype formed by these quadruple mutations predominated in Yingjiang, Tengchong, Longling and Nabang. While a mutation H99S/R (56.6%) dominated in Laiza and increased with time. In pvdhps, the A383G prevailed in 69.2% of the samples, which remained the most prevalent haplotype. However, a significant decrease of its occurrence was also noticed over the time. The S382A/C and A553G existed in 8.4% and 30.8% of the isolates, respectively. In pvmdr1, the mutation Y976F occurred at a low frequency in 5/232 (2.2%), while T958M was fixed and F1076L was approaching fixed (72.4%). The K10 insertion was detected at an occurrence of 33.2% in pvcrt-o, whereas there was no significant difference among the sites or over the time. No mutation was identified in pvk12.ConclusionsMutations related with resistance to antifolate drugs are prevalent in this area, while their frequencies decrease significantly with time, suggestive of increased susceptibility of P. vivax parasite to antifolate drugs. Resistance to chloroquine (CQ) is possibly emerging. However, since the molecular mechanisms underneath CQ resistance is yet to be better understood, close supervision of clinical drug efficiency and continuous function investigation is urgently needed to alarm drug resistance.

Dataset Information

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

Publications

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

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