Polymorphism of antifolate drug resistance in Plasmodium vivax from local residents and migrant workers returned from the China-Myanmar Border

Authors: FENG, SHI - Kunming Medical University; WANG, SIQI - Kunming Medical University; ZENG, WELIN - Kunming Medical University; ZHONG, DAIBIN - University Of California; HU, YUE - Kunming Medical University; BAI, YAO - Kunming Medical University; RUAN, YONGHUA - Kunming Medical University; SI, YU - Kunming Medical University; ZHAO, HUI - Kunming Medical University; YANG, QI - Kunming Medical University; LI, XINXIN - Kunming Medical University; CHEN, XI - Kunming Medical University; ZHANG, YANMEI - Kunming Medical University; LI, CUIYING - Kunming Medical University; XIANG, ZHENG - Kunming Medical University; WU, YANRUI - Kunming Medical University; CHENG, FANG - Kunming Medical University; SU, PINCAN - Kunming Medical University; Rosenthal, Benjamin; YANG, ZHAOQING - Kunming Medical University

Submitted to: PLOS Neglected Tropical Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/3/2021
Publication Date: 6/24/2021
Citation: Feng, S., Wang, S., Zeng, W., Zhong, D., Hu, Y., Bai, Y., Ruan, Y., Si, Y., Zhao, H., Yang, Q., Li, X., Chen, X., Zhang, Y., Li, C., Xiang, Z., Wu, Y., Cheng, F., Su, P., Rosenthal, B.M., Yang, Z. 2021. Polymorphism of antifolate drug resistance in Plasmodium vivax from local residents and migrant workers returned from the China-Myanmar Border. PLOS Neglected Tropical Diseases. 11:683423. https://doi.org/10.3389/fcimb.2021.683423.
DOI: https://doi.org/10.3389/fcimb.2021.683423

Interpretive Summary: Anti-parasitic drugs play an important role in managing threats to animal and human health, but their over-use leads to resistance. Restricting therapies to targeted uses can prolong the efficacy of a drug, but real-world difficulties can undermine such strategic application. For example, optimal treatment of one type of malaria (cause by the parasite Plasmodium vivax) no longer works for another type of malaria (Plasmodium falciparum). But frequent (often undiagnosed) co-infections mean that treatment intended for one parasite can impose selection for drug resistance in the other. Such a situation is common for livestock species incurring infection with parasite mixtures. Here, the problem was examined in people exposed to mixed malaria infections. The research team documented extensive evidence that the 'off target' parasite has evolved resistance to drugs commonly intended to control the other. The results will interest those attempting to safeguard human health and eradicate seasonal malaria in Asia, but have consequences for veterinary health and public health wherever drug treatments is applied without sufficient diagnostic precision.

Technical 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 (FST = 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.