Plasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross

Juliana M. Sá, Sarah R. Kaslow, Roberto R. Moraes Barros, Nicholas F. Brazeau, Christian M. Parobek, Dingyin Tao, Rebecca E. Salzman, Tyler J. Gibson, Soundarapandian Velmurugan, Michael A. Krause, Viviana Melendez-Muniz, Whitney A. Kite, Paul K. Han, Richard T. Eastman, Adam Kim, Evan G. Kessler, Yonas Abebe, Eric R. James, Sumana Chakravarty, Sachy Orr-GonzalezLynn E. Lambert, Theresa Engels, Marvin L. Thomas, Pius S. Fasinu, David Serre, Robert W. Gwadz, Larry Walker, Derrick K. DeConti, Jianbing Mu, Jeffrey A. Bailey, B. Kim Lee Sim, Stephen L. Hoffman, Michael P. Fay, Rhoel R. Dinglasan, Jonathan J. Juliano, Thomas E. Wellems

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Mainstay treatment for Plasmodium vivax malaria has long relied on chloroquine (CQ) against blood-stage parasites plus primaquine against dormant liver-stage forms (hypnozoites), however drug resistance confronts this regimen and threatens malaria control programs. Understanding the basis of P. vivax chloroquine resistance (CQR) will inform drug discovery and malaria control. Here we investigate the genetics of P. vivax CQR by a cross of parasites differing in drug response. Gametocytogenesis, mosquito infection, and progeny production are performed with mixed parasite populations in nonhuman primates, as methods for P. vivax cloning and in vitro cultivation remain unavailable. Linkage mapping of progeny surviving >15 mg/kg CQ identifies a 76 kb region in chromosome 1 including pvcrt, an ortholog of the Plasmodium falciparum CQR transporter gene. Transcriptional analysis supports upregulated pvcrt expression as a mechanism of CQR.

Original languageEnglish (US)
Article number4300
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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