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; Thomas E. Wellems

doi:10.1038/s41467-019-12256-9

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

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30 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 language	English (US)
Article number	4300
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12256-9
State	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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10.1038/s41467-019-12256-9

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Sá, J. M., Kaslow, S. R., Moraes Barros, R. R., Brazeau, N. F., Parobek, C. M., Tao, D., Salzman, R. E., Gibson, T. J., Velmurugan, S., Krause, M. A., Melendez-Muniz, V., Kite, W. A., Han, P. K., Eastman, R. T., Kim, A., Kessler, E. G., Abebe, Y., James, E. R., Chakravarty, S., ... Wellems, T. E. (2019). Plasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross. Nature communications, 10(1), Article 4300. https://doi.org/10.1038/s41467-019-12256-9

Sá, JM, Kaslow, SR, Moraes Barros, RR, Brazeau, NF, Parobek, CM, Tao, D, Salzman, RE, Gibson, TJ, Velmurugan, S, Krause, MA, Melendez-Muniz, V, Kite, WA, Han, PK, Eastman, RT, Kim, A, Kessler, EG, Abebe, Y, James, ER, Chakravarty, S, Orr-Gonzalez, S, Lambert, LE, Engels, T, Thomas, ML, Fasinu, PS, Serre, D, Gwadz, RW, Walker, L, DeConti, DK, Mu, J, Bailey, JA, Sim, BKL, Hoffman, SL, Fay, MP, Dinglasan, RR, Juliano, JJ & Wellems, TE 2019, 'Plasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross', Nature communications, vol. 10, no. 1, 4300. https://doi.org/10.1038/s41467-019-12256-9

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title = "Plasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross",

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.",

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note = "Publisher Copyright: {\textcopyright} 2019, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

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AU - Sá, Juliana M.

AU - Kaslow, Sarah R.

AU - Moraes Barros, Roberto R.

AU - Brazeau, Nicholas F.

AU - Parobek, Christian M.

AU - Tao, Dingyin

AU - Salzman, Rebecca E.

AU - Gibson, Tyler J.

AU - Velmurugan, Soundarapandian

AU - Krause, Michael A.

AU - Melendez-Muniz, Viviana

AU - Kite, Whitney A.

AU - Han, Paul K.

AU - Eastman, Richard T.

AU - Kim, Adam

AU - Kessler, Evan G.

AU - Abebe, Yonas

AU - James, Eric R.

AU - Chakravarty, Sumana

AU - Orr-Gonzalez, Sachy

AU - Lambert, Lynn E.

AU - Engels, Theresa

AU - Thomas, Marvin L.

AU - Fasinu, Pius S.

AU - Serre, David

AU - Gwadz, Robert W.

AU - Walker, Larry

AU - DeConti, Derrick K.

AU - Mu, Jianbing

AU - Bailey, Jeffrey A.

AU - Sim, B. Kim Lee

AU - Hoffman, Stephen L.

AU - Fay, Michael P.

AU - Dinglasan, Rhoel R.

AU - Juliano, Jonathan J.

AU - Wellems, Thomas E.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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

Abstract

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