Plasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross.
Juliana M SáSarah R KaslowRoberto R Moraes BarrosNicholas F BrazeauChristian M ParobekDingyin TaoRebecca E SalzmanTyler J GibsonSoundarapandian VelmuruganMichael A KrauseViviana Melendez-MunizWhitney A KitePaul K HanRichard T EastmanAdam KimEvan G KesslerYonas AbebeEric R JamesSumana ChakravartySachy Orr-GonzalezLynn E LambertTheresa EngelsMarvin L ThomasPius S FasinuDavid SerreRobert W GwadzLarry A WalkerDerrick K DeContiJianbing MuJeffrey A BaileyB Kim Lee SimStephen L HoffmanMichael P FayRhoel R DinglasanJonathan J JulianoThomas E WellemsPublished in: Nature communications (2019)
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.
Keyphrases
- plasmodium falciparum
- genome wide
- drug discovery
- copy number
- poor prognosis
- transcription factor
- dna methylation
- public health
- gene expression
- high resolution
- emergency department
- aedes aegypti
- dengue virus
- high density
- mass spectrometry
- long non coding rna
- hiv testing
- hepatitis c virus
- drug induced
- men who have sex with men
- genetic diversity
- genome wide identification