非洲恶性疟原虫分离株中 pfact、pfugt 和 pfcarl 基因的低多态性与常见抗疟药物敏感性无关。

Low polymorphisms in pfact, pfugt and pfcarl genes in African Plasmodium falciparum isolates and absence of association with susceptibility to common anti-malarial drugs.

机构信息

Unité Parasitologie et Entomologie, Département de Microbiologie et de maladies infectieuses, Institut de recherche biomédicale des armées, IHU Méditerranée Infection, 19-21 Boulevard Jean Moulin, 13005, Marseille, France.

IRD, SSA, AP-HM, VITROME, Aix Marseille Université, Marseille, France.

出版信息

Malar J. 2019 Aug 28;18(1):293. doi: 10.1186/s12936-019-2919-3.

DOI:10.1186/s12936-019-2919-3

PMID:31455301

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6712813/

Abstract

BACKGROUND

Resistance to all available anti-malarial drugs has emerged and spread including artemisinin derivatives and their partner drugs. Several genes involved in artemisinin and partner drugs resistance, such as pfcrt, pfmdr1, pfK13 or pfpm2, have been identified. However, these genes do not properly explain anti-malarial drug resistance, and more particularly clinical failures observed in Africa. Mutations in genes encoding for Plasmodium falciparum proteins, such as P. falciparum Acetyl-CoA transporter (PfACT), P. falciparum UDP-galactose transporter (PfUGT) and P. falciparum cyclic amine resistance locus (PfCARL) have recently been associated to resistance to imidazolopiperazines and other unrelated drugs.

METHODS

Mutations on pfugt, pfact and pfcarl were characterized on 86 isolates collected in Dakar, Senegal and 173 samples collected from patients hospitalized in France after a travel in African countries from 2015 and 2016 to assess their potential association with ex vivo susceptibility to chloroquine, quinine, lumefantrine, monodesethylamodiaquine, mefloquine, dihydroartemisinin, artesunate, doxycycline, pyronaridine and piperaquine.

RESULTS

No mutations were found on the genes pfugt and pfact. None of the pfcarl described mutations were identified in these samples from Africa. The K784N mutation was found in one sample and the K734M mutation was identified on 7.9% of all samples for pfcarl. The only significant differences in ex vivo susceptibility according to the K734M mutation were observed for pyronaridine for African isolates from imported malaria and for doxycycline for Senegalese parasites.

CONCLUSION

No evidence was found of involvement of these genes in reduced susceptibility to standard anti-malarial drugs in African P. falciparum isolates.

摘要

背景

包括青蒿素衍生物及其联合用药在内的所有现有抗疟药物的耐药性已经出现并传播。已经鉴定出几种与青蒿素和联合用药耐药性相关的基因，如 pfcrt、pfmdr1、pfK13 或 pfpm2。然而，这些基因并不能很好地解释抗疟药物耐药性，特别是在非洲观察到的临床失败。最近，与咪唑并哌嗪类和其他不相关药物耐药性相关的是编码疟原虫蛋白的基因（如疟原虫乙酰辅酶 A 转运蛋白（PfACT）、疟原虫 UDP-半乳糖转运蛋白（PfUGT）和疟原虫环胺耐药基因座（PfCARL））的突变。

方法

对 86 株在塞内加尔达喀尔采集的分离株和 173 株从 2015 年至 2016 年在非洲国家旅行后在法国住院的患者中采集的样本进行了 pfugt、pfact 和 pfcarl 的突变特征分析，以评估它们与氯喹、奎宁、青蒿琥酯、去乙基阿莫地喹、甲氟喹、二氢青蒿素、青蒿琥酯、强力霉素、匹那喹和哌喹的体外敏感性的潜在相关性。

结果

在 pfugt 和 pfact 基因上未发现突变。在这些来自非洲的样本中，没有发现描述的 pfcarl 基因突变。在一个样本中发现了 K784N 突变，在所有样本中，K734M 突变在 7.9%的样本中被鉴定出来。只有 K734M 突变与吡喹酮对进口疟疾病原虫和强力霉素对塞内加尔寄生虫的体外敏感性有显著差异。