Origin and Evolution of Sulfadoxine Resistant Plasmodium falciparum

PLoS Pathogens

Sumiti Vinayak¹  Sinuon Muth²  William O. Rogers³  Venkatachalam Udhayakumar³  Ananias A. Escalante⁴  Tonya Mixson-Hayden⁵  Rithy Sem⁵  Md Tauqeer Alam⁵  Chansuda Wongsrichanalai⁵  Andrea M. McCollum⁵  Thierry Fandeur⁶  Naman K. Shah⁶  Frederick Ariey⁷  John W. Barnwell⁸  Pharath Lim⁸  Steven R. Meshnick⁸ 

[1] Atlanta Research and Education Foundation, Atlanta, Georgia, United States of America;Department of Epidemiology, UNC School of Public Health, Chapel Hill, North Carolina, United States of America;Institut Pasteur in Cambodia, Phnom Penh, Cambodia;Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Paris, France;Malaria Branch, Division of Parasitic Diseases, National Center for Zoonotic Vector Borne and Enteric Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America;National Malaria Center, Phnom Penh, Cambodia;School of Life Sciences, Arizona State University, Tempe, Arizona, United States of America;US Naval Medical Research Unit No. 2, Jakarta, Indonesia

关键词: Genetic loci;    Cambodia;    Haplotypes;    Antimicrobial resistance;    Mutation;    Microsatellite loci;    Alleles;    Malaria;   

DOI  :  10.1371/journal.ppat.1000830

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The Thailand-Cambodia border is the epicenter for drug-resistant falciparum malaria. Previous studies have shown that chloroquine (CQ) and pyrimethamine resistance originated in this region and eventually spread to other Asian countries and Africa. However, there is a dearth in understanding the origin and evolution of dhps alleles associated with sulfadoxine resistance. The present study was designed to reveal the origin(s) of sulfadoxine resistance in Cambodia and its evolutionary relationship to African and South American dhps alleles. We sequenced 234 Cambodian Plasmodium falciparum isolates for the dhps codons S436A/F, A437G, K540E, A581G and A613S/T implicated in sulfadoxine resistance. We also genotyped 10 microsatellite loci around dhps to determine the genetic backgrounds of various alleles and compared them with the backgrounds of alleles prevalent in Africa and South America. In addition to previously known highly-resistant triple mutant dhps alleles SGEGA and AGEAA (codons 436, 437, 540, 581, 613 are sequentially indicated), a large proportion of the isolates (19.3%) contained a 540N mutation in association with 437G/581G yielding a previously unreported triple mutant allele, SGNGA. Microsatellite data strongly suggest the strength of selection was greater on triple mutant dhps alleles followed by the double and single mutants. We provide evidence for at least three independent origins for the double mutants, one each for the SGKGA, AGKAA and SGEAA alleles. Our data suggest that the triple mutant allele SGEGA and the novel allele SGNGA have common origin on the SGKGA background, whereas the AGEAA triple mutant was derived from AGKAA on multiple, albeit limited, genetic backgrounds. The SGEAA did not share haplotypes with any of the triple mutants. Comparative analysis of the microsatellite haplotypes flanking dhps alleles from Cambodia, Kenya, Cameroon and Venezuela revealed an independent origin of sulfadoxine resistant alleles in each of these regions.

【 授权许可】

CC BY