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-Gonzalez, Lynn 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 and Thomas E. Wellems ()
Additional contact information
Juliana M. Sá: National Institutes of Health
Sarah R. Kaslow: National Institutes of Health
Roberto R. Moraes Barros: National Institutes of Health
Nicholas F. Brazeau: University of North Carolina
Christian M. Parobek: University of North Carolina at Chapel Hill
Dingyin Tao: Johns Hopkins Bloomberg School of Public Health
Rebecca E. Salzman: National Institutes of Health
Tyler J. Gibson: National Institutes of Health
Soundarapandian Velmurugan: Sanaria Inc.
Michael A. Krause: National Institutes of Health
Viviana Melendez-Muniz: National Institutes of Health
Whitney A. Kite: National Institutes of Health
Paul K. Han: National Institutes of Health
Richard T. Eastman: National Institutes of Health
Adam Kim: University of Maryland School of Medicine
Evan G. Kessler: National Institutes of Health
Yonas Abebe: Sanaria Inc.
Eric R. James: Sanaria Inc.
Sumana Chakravarty: Sanaria Inc.
Sachy Orr-Gonzalez: National Institutes of Health
Lynn E. Lambert: National Institutes of Health
Theresa Engels: National Institutes of Health
Marvin L. Thomas: National Institutes of Health
Pius S. Fasinu: Campbell University
David Serre: University of Maryland School of Medicine
Robert W. Gwadz: National Institutes of Health
Larry Walker: Campbell University
Derrick K. DeConti: University of Massachusetts Medical School
Jianbing Mu: National Institutes of Health
Jeffrey A. Bailey: Campbell University
B. Kim Lee Sim: Sanaria Inc.
Stephen L. Hoffman: Sanaria Inc.
Michael P. Fay: National Institutes of Health
Rhoel R. Dinglasan: Johns Hopkins Bloomberg School of Public Health
Jonathan J. Juliano: University of North Carolina
Thomas E. Wellems: National Institutes of Health

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12256-9

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