Chan Chim W, Lynch Daniel, Spathis Rita, Hombhanje Francis W, Kaneko Akira, Garruto Ralph M, Lum J Koji
Laboratory of Evolutionary Anthropology and Health, Binghamton University, Binghamton, NY 13902-6000, USA.
Acta Trop. 2006 Aug;99(1):15-22. doi: 10.1016/j.actatropica.2006.05.011. Epub 2006 Aug 7.
The increasing frequencies of Plasmodium falciparum strains that are resistant to chloroquine (CQ) and other antimalarials are resulting in a global resurgence of malaria morbidity and mortality. CQ resistance (CQR) is associated with multiple mutations in the P. falciparum chloroquine resistance transporter (pfcrt) gene. The mode and tempo of the accumulation of substitutions leading to these complex CQR haplotypes remain speculative due to the dearth of samples temporally spanning the evolution of drug resistance. The origin and evolution of the CQR alleles of Papua New Guinea (PNG) is particularly ambiguous. It remains unclear whether the pfcrt haplotype in PNG resulted from an independent origin of a CQR haplotype identical in sequence to the South American haplotype, or if this haplotype originated in South America and recombined into a Southeast Asian-derived genome. We sequenced a segment of pfcrt exon 2 from 398 plasmid clones derived from archival human sera collected in the Pacific before and after the first reported cases of CQ treatment failure (n=251) and modern samples (n=147). None of the 251 pfcrt plasmid clones from nine archival samples displayed the C72S or the K76T mutations that are characteristic of CQR strains. In contrast, these two amino acid substitutions were present in all 147 pfcrt plasmid clones from five samples collected between 2001 and 2003; thus, the archival samples represent the baseline parasite genetic diversity before the evolution of CQR strains. We are currently expanding our analyses to include additional samples from the series described here and from series collected in the 1970s and the 1980s to evaluate the geographic origin of CQR strains in the Pacific and the validity of the sequential point mutation accumulation model of CQR evolution.
对氯喹（CQ）和其他抗疟药物产生耐药性的恶性疟原虫菌株频率不断增加，导致全球疟疾发病率和死亡率再度上升。CQ耐药性（CQR）与恶性疟原虫氯喹耐药转运蛋白（pfcrt）基因的多个突变相关。由于缺乏跨越耐药性演变时间的样本，导致这些复杂CQR单倍型的替代积累模式和速度仍属推测。巴布亚新几内亚（PNG）CQR等位基因的起源和演变尤其不明确。目前尚不清楚PNG的pfcrt单倍型是源于与南美单倍型序列相同的CQR单倍型的独立起源，还是该单倍型起源于南美并重组到东南亚衍生的基因组中。我们对398个质粒克隆的pfcrt外显子2片段进行了测序，这些克隆来自在首次报告CQ治疗失败之前和之后在太平洋地区采集的存档人类血清（n = 251）以及现代样本（n = 147）。来自9个存档样本的251个pfcrt质粒克隆均未显示出CQR菌株特有的C72S或K76T突变。相比之下，在2001年至2003年期间采集的5个样本的所有147个pfcrt质粒克隆中都存在这两个氨基酸替代；因此，存档样本代表了CQR菌株进化之前的基线寄生虫遗传多样性。我们目前正在扩大分析范围，纳入此处描述系列以及20世纪70年代和80年代采集系列的更多样本，以评估太平洋地区CQR菌株的地理起源以及CQR进化的顺序点突变积累模型的有效性。
