Mehlotra R K, Fujioka H, Roepe P D, Janneh O, Ursos L M, Jacobs-Lorena V, McNamara D T, Bockarie M J, Kazura J W, Kyle D E, Fidock D A, Zimmerman P A
Division of Geographic Medicine, Case Western Reserve University, University Hospitals of Cleveland, School of Medicine, W147D, 2109 Adelbert Road, Cleveland, OH 44106-4983, USA.
Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12689-94. doi: 10.1073/pnas.221440898.
The mechanistic basis for chloroquine resistance (CQR) in Plasmodium falciparum recently has been linked to the polymorphic gene pfcrt. Alleles associated with CQR in natural parasite isolates harbor threonine (T), as opposed to lysine (K) at amino acid 76. P. falciparum CQR strains of African and Southeast Asian origin carry pfcrt alleles encoding an amino acid haplotype of CVIET (residues 72-76), whereas most South American CQR strains studied carry an allele encoding an SVMNT haplotype; chloroquine-sensitive strains from malarious regions around the world carry a CVMNK haplotype. Upon investigating the origin of pfcrt alleles in Papua New Guinean (PNG) P. falciparum we found either the chloroquine-sensitive-associated CVMNK or CQR-associated SVMNT haplotypes previously seen in Brazilian isolates. Remarkably we did not find the CVIET haplotype observed in CQR strains from Southeast Asian regions more proximal to PNG. Further we found a previously undescribed CQR phenotype to be associated with the SVMNT haplotype from PNG and South America. This CQR phenotype is significantly less responsive to verapamil chemosensitization compared with the effect associated with the CVIET haplotype. Consistent with this, we observed that verapamil treatment of P. falciparum isolates carrying pfcrt SVMNT is associated with an attenuated increase in digestive vacuole pH relative to CVIET pfcrt-carrying isolates. These data suggest a key role for pH-dependent changes in hematin receptor concentration in the P. falciparum CQR mechanism. Our findings also suggest that P. falciparum CQR has arisen through multiple evolutionary pathways associated with pfcrt K76T.
恶性疟原虫对氯喹耐药性（CQR）的机制基础最近已与多态性基因pfcrt联系起来。与天然寄生虫分离株中CQR相关的等位基因在氨基酸76处携带苏氨酸（T），而非赖氨酸（K）。非洲和东南亚起源的恶性疟原虫CQR菌株携带编码CVIET氨基酸单倍型（残基72 - 76）的pfcrt等位基因，而大多数研究的南美CQR菌株携带编码SVMNT单倍型的等位基因；来自世界各地疟疾流行地区的氯喹敏感菌株携带CVMNK单倍型。在调查巴布亚新几内亚（PNG）恶性疟原虫中pfcrt等位基因的起源时，我们发现了之前在巴西分离株中看到的与氯喹敏感相关的CVMNK或与CQR相关的SVMNT单倍型。值得注意的是，我们没有在离PNG更近的东南亚地区的CQR菌株中发现观察到的CVIET单倍型。此外，我们发现一种先前未描述的CQR表型与来自PNG和南美的SVMNT单倍型相关。与CVIET单倍型相关的效应相比，这种CQR表型对维拉帕米化学增敏的反应明显较弱。与此一致的是，我们观察到用维拉帕米处理携带pfcrt SVMNT的恶性疟原虫分离株时，相对于携带CVIET pfcrt的分离株，消化泡pH值的升高减弱。这些数据表明血红素受体浓度的pH依赖性变化在恶性疟原虫CQR机制中起关键作用。我们的研究结果还表明，恶性疟原虫CQR是通过与pfcrt K76T相关的多种进化途径产生的。
