pfcrt allelic types with two novel amino acid mutations in chloroquine-resistant Plasmodium falciparum isolates from the Philippines
pfcrt allelic types with two novel amino acid mutations in chloroquine-resistant Plasmodium falciparum isolates from the Philippines
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DOI：
10.1128/aac.47.11.3500-3505.2003
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发表时间：
2003-11-01
影响因子：
4.9
通讯作者：
Cheng, Q
中科院分区：
文献类型：
--
作者：
Chen, NH;Kyle, DE;Cheng, Q
pfcrt和pfmdr1基因的突变与恶性疟原虫的氯喹耐药性有关。在这些基因中分别发现了10个和5个突变，这些突变来自世界各地的氯喹抗性寄生虫。pfcrt的突变模式表明，氯喹耐药性在东南亚、南美和巴布亚新几内亚独立进化。然而，太平洋其他地区氯喹耐药性的演变尚不清楚。在这项研究中，我们检测了菲律宾Morong分离株中这些基因的序列多态性，并将其与已知的氯喹抗性序列进行了比较。在莫荣分离株的pfcrt中，除了已知的10个突变外，还发现了两个新的突变，A144T和L160Y。这些新突变仅在携带K76T和N326D的寄生虫中发现，而没有在大多数氯喹耐药菌株中发现的常见A220S突变。这代表了一种独特的氯喹抗性等位基因类型（K76T/A144T/L160Y/N326D），以前在世界其他地方未发现。一株莫荣分离株还具有额外的C72S突变，而在亚洲只有一株分离株具有氯喹耐药的典型等位基因类型。具有新型pfcrt等位基因型的寄生虫体外对氯喹耐药，对维拉帕米（0.9 muM）化学致敏无反应，与南美和巴布亚新几内亚的氯喹耐药寄生虫相似。这些结果表明，氯喹耐药性在菲律宾独立进化，代表了南太平洋的第二次氯喹耐药性创始事件。
Mutations in the pfcrt and pfmdr1 genes have been associated with chloroquine resistance in Plasmodium falciparum. Ten and five mutations, respectively, have been identified in these genes from chloroquine-resistant parasites worldwide. Mutation patterns in pfcrt revealed that chloroquine resistance evolved independently in southeast Asia, South America, and Papua New Guinea. However, the evolution of chloroquine resistance in the rest of the Pacific region is unclear. In this study, we examined sequence polymorphisms in these genes in isolates from Morong, Philippines, and compared them to known chloroquine resistance sequences. Two novel mutations, A144T and L160Y, were identified outside of the 10 known mutations in pfcrt in Morong isolates. These novel mutations were identified only in parasites with K76T and N326D but without the common A220S mutation found in most chloroquine-resistant isolates. This represents a unique chloroquine resistance allelic type (K76T/A144T/L160Y/N326D) not previously found elsewhere in the world. One Morong isolate also had an additional C72S mutation, whereas only one isolate possessed an allelic type typical of chloroquine resistance in Asia. Parasites with the novel pfcrt allelic types were resistant to chloroquine in vitro and were unresponsive to verapamil (0.9 muM) chemosensitization, similar to chloroquine-resistant parasites from South America and Papua New Guinea. These results suggest that chloroquine resistance evolved independently in the Philippines and represents a second chloroquine resistance founder event in the South Pacific.