AUTHOR=Zeng Weilin , Wang Siqi , Feng Shi , Zhong Daibin , Hu Yue , Bai Yao , Ruan Yonghua , Si Yu , Zhao Hui , Yang Qi , Li Xinxin , Chen Xi , Zhang Yanmei , Li Cuiying , Xiang Zheng , Wu Yanrui , Chen Fang , Su Pincan , Rosenthal Benjamin M. , Yang Zhaoqing 

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.683423

DOI=10.3389/fcimb.2021.683423

ISSN=2235-2988

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