德国Bernhard Nocht热带医学研究所Tobias Spielmann研究小组近日发现，Kelch13定义的内吞途径介导疟原虫对青蒿素的抗性。这一研究成果2020年1月3日发表在国际学术期刊《科学》上。

研究人员鉴定了位于Kelch13所定义的区室内的蛋白质。包括Kelch13在内的8种蛋白质的失活使寄生虫对青蒿素及其衍生物（ART）产生耐药性，从而揭示了抗药性的关键途径。 功能分析表明，这些蛋白质是从宿主细胞内吞血红蛋白所需的。具有失活Kelch13或产生抗性Kelch13突变的寄生虫显示出血红蛋白内吞减少。ART被血红蛋白的降解产物激活。因此，Kelch13及其相互作用蛋白活性的降低能够减少血红蛋白的内吞作用，从而减少ART的激活，最终导致了寄生虫的耐药。

据了解，ART是抗疟疾的第一线药物，但耐药性正在损害其有效性。抗药性是由寄生虫的Kelch13蛋白突变介导的，但尚不清楚Kelch13的功能及其在抗药性中的作用。

附：英文原文

Title: A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites

Author: Jakob Birnbaum, Sarah Scharf, Sabine Schmidt, Ernst Jonscher, Wieteke Anna Maria Hoeijmakers, Sven Flemming, Christa Geeke Toenhake, Marius Schmitt, Ricarda Sabitzki, Brbel Bergmann, Ulrike Frhlke, Paolo Mesén-Ramírez, Alexandra Blancke Soares, Hendrik Herrmann, Richárd Bártfai, Tobias Spielmann

Issue&Volume: 2020/01/03

Abstract: Artemisinin and its derivatives (ARTs) are the frontline drugs against malaria, but resistance is jeopardizing their effectiveness. ART resistance is mediated by mutations in the parasite’s Kelch13 protein, but Kelch13 function and its role in resistance remain unclear. In this study, we identified proteins located at a Kelch13-defined compartment. Inactivation of eight of these proteins, including Kelch13, rendered parasites resistant to ART, revealing a pathway critical for resistance. Functional analysis showed that these proteins are required for endocytosis of hemoglobin from the host cell. Parasites with inactivated Kelch13 or a resistance-conferring Kelch13 mutation displayed reduced hemoglobin endocytosis. ARTs are activated by degradation products of hemoglobin. Hence, reduced activity of Kelch13 and its interactors diminishes hemoglobin endocytosis and thereby ART activation, resulting in parasite resistance.

DOI: 10.1126/science.aax4735

Source: https://science.sciencemag.org/content/367/6473/51