Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
Nat Commun. 2019 Sep 20;10(1):4300. doi: 10.1038/s41467-019-12256-9.
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.
根治间日疟原虫的主要方法一直以来都是使用氯喹（CQ）来杀灭血期疟原虫，同时使用伯氨喹来杀灭休眠的肝期疟原虫（休眠子），然而，这种疗法已经面临耐药性的挑战，威胁着疟疾控制项目。了解间日疟原虫对氯喹的耐药性（CQR）的基础将为药物发现和疟疾控制提供信息。在这里，我们通过对药物反应不同的寄生虫进行杂交，来研究间日疟原虫 CQR 的遗传学。通过在非人类灵长类动物中进行混合寄生虫群的配子发生、蚊子感染和后代产生，来进行间日疟原虫的克隆和体外培养，因为这些方法仍然不可用。对后代的连锁图谱进行分析，这些后代在 15 毫克/千克 CQ 以上的药物浓度下能够存活，结果确定了 1 号染色体上的一个 76kb 区域，其中包括 pvcrt，它是恶性疟原虫 CQR 转运蛋白基因的同源物。转录分析支持上调 pvcrt 表达作为 CQR 的一种机制。
