Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System-DEID-GEIS Program, United States Army Medical Research Unit-Kenya-USAMRU-K, Nairobi, Kenya.
PLoS One. 2013 May 13;8(5):e64299. doi: 10.1371/journal.pone.0064299. Print 2013.
Single Nucleotide Polymorphisms (SNPs) in the Pfmdr1, and Pfcrt, genes of Plasmodium falciparum may confer resistance to a number of anti-malaria drugs. Pfmdr1 86Y and haplotypes at Pfcrt 72-76 have been linked to chloroquine (CQ) as well as amodiaquine (AQ) resistance. mefloquine (MQ) and lumefantrine (LU) sensitivities are linked to Pfmdr1 86Y. Additionally, Pfcrt K76 allele carrying parasites have shown tolerance to LU. We investigated the association between Pfmdr1 86/Pfcrt 72-76 and P. falciparum resistance to CQ, AQ, MQ and LU using field samples collected during 2008-2011 from malaria endemic sites in western Kenya. Genomic DNA from these samples was genotyped to examine SNPs and haplotypes in Pfmdr1 and Pfcrt respectively. Additionally, immediate ex vivo and in vitro drug sensitivity profiles were assessed using the malaria SYBR Green I fluorescence-based assay. We observed a rapid but steady percent increase in wild-type parasites with regard to both Pfmdr1 and Pfcrt between 2008 and 2011 (p<0.0001). Equally, a significant reciprocate decrease in AQ and CQ median IC50 values occurred (p<0.0001) during the same period. Thus, the data in this study point to a significantly rapid change in parasite response to AQ and CQ in the study period. This may be due to releasing of drug pressure on the parasite from reduced use of AQ in the face of increased Artemisinin (ART) Combination Therapy (ACT) administration following the intervention of the Global Fund in 2008. LU has been shown to select for 76K genotypes, thus the observed increase in 76K genotypes coupled with significant cross resistance between LU and MQ, may herald emergence of tolerance against both drugs in future.
疟原虫 Pfmdr1 和 Pfcrt 基因中的单核苷酸多态性（SNPs）可能导致对多种抗疟药物的耐药性。Pfmdr1 86Y 和 Pfcrt 72-76 处的单倍型与氯喹（CQ）以及阿莫地喹（AQ）耐药性有关。甲氟喹（MQ）和青蒿琥酯（LU）敏感性与 Pfmdr1 86Y 有关。此外，携带 Pfcrt K76 等位基因的寄生虫对 LU 表现出耐受性。我们利用 2008 年至 2011 年在肯尼亚西部疟疾流行地区采集的现场样本，研究 Pfmdr1 86/Pfcrt 72-76 与疟原虫对 CQ、AQ、MQ 和 LU 的耐药性之间的关系。对这些样本的基因组 DNA 进行基因分型，以分别检测 Pfmdr1 和 Pfcrt 中的 SNPs 和单倍型。此外，还使用疟疾 SYBR Green I 荧光法即时评估体外和体内药物敏感性谱。我们观察到，2008 年至 2011 年间，Pfmdr1 和 Pfcrt 野生型寄生虫的比例迅速但稳定增加（p<0.0001）。同样，同期 AQ 和 CQ 中位数 IC50 值也显著下降（p<0.0001）。因此，本研究中的数据表明，在研究期间，寄生虫对 AQ 和 CQ 的反应迅速发生变化。这可能是由于全球基金于 2008 年干预后，AQ 的使用减少，而青蒿素（ART）联合疗法（ACT）的使用增加，从而减轻了对寄生虫的药物压力。LU 已被证明选择 76K 基因型，因此观察到的 76K 基因型增加以及 LU 和 MQ 之间的交叉耐药性增加，可能预示着未来对这两种药物的耐受性出现。
