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Artemisinin susceptibility in the malaria parasite Plasmodium falciparum: propellers, adaptor proteins and the need for cellular healing.
FEMS Microbiology Reviews ( IF 10.1 ) Pub Date : 2021-05-05 , DOI: 10.1093/femsre/fuaa056
Colin J Sutherland 1 , Ryan C Henrici 1, 2 , Katerina Artavanis-Tsakonas 3
Affiliation  

Studies of the susceptibility of Plasmodium falciparum to the artemisinin family of antimalarial drugs provide a complex picture of partial resistance (tolerance) associated with increased parasite survival in vitro and in vivo. We present an overview of the genetic loci that, in mutant form, can independently elicit parasite tolerance. These encode Kelch propeller domain protein PfK13, ubiquitin hydrolase UBP-1, actin filament-organising protein Coronin, also carrying a propeller domain, and the trafficking adaptor subunit AP-2μ. Detailed studies of these proteins and the functional basis of artemisinin tolerance in blood-stage parasites are enabling a new synthesis of our understanding to date. To guide further experimental work, we present two major conclusions. First, we propose a dual-component model of artemisinin tolerance in P. falciparum comprising suppression of artemisinin activation in early ring stage by reducing endocytic haemoglobin capture from host cytosol, coupled with enhancement of cellular healing mechanisms in surviving cells. Second, these two independent requirements limit the likelihood of development of complete artemisinin resistance by P. falciparum, favouring deployment of existing drugs in new schedules designed to exploit these biological limits, thus extending the useful life of current combination therapies.

中文翻译:


疟原虫恶性疟原虫中的青蒿素敏感性:螺旋桨、衔接蛋白和细胞愈合的需要。



关于恶性疟原虫对青蒿素家族抗疟药物的敏感性的研究提供了与体外和体内寄生虫存活率增加相关的部分耐药性(耐受性)的复杂情况。我们概述了突变形式下可以独立引发寄生虫耐受性的遗传位点。它们编码 Kelch 螺旋桨结构域蛋白 PfK13、泛素水解酶 UBP-1、肌动蛋白丝组织蛋白 Coronin(也携带螺旋桨结构域)和运输接头亚基 AP-2μ。对这些蛋白质的详细研究以及血液阶段寄生虫中青蒿素耐受性的功能基础使我们能够对迄今为止的理解进行新的综合。为了指导进一步的实验工作,我们提出两个主要结论。首先,我们提出了恶性疟原虫青蒿素耐受的双组分模型,包括通过减少宿主细胞质中的内吞血红蛋白捕获来抑制早期环期青蒿素活化,同时增强存活细胞的细胞愈合机制。其次,这两个独立的要求限制了恶性疟原虫产生完全青蒿素耐药性的可能性,有利于在旨在利用这些生物学限制的新方案中部署现有药物,从而延长当前联合疗法的使用寿命。
更新日期:2021-05-05
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