Institut Pasteur, Université de Paris, Malaria Parasite Biology and Vaccines Unit, Paris, France.
Institut Pasteur, Université de Paris, Malaria Infection and Immunity Unit, Paris, France.
Cell Rep. 2022 Jun 14;39(11):110923. doi: 10.1016/j.celrep.2022.110923.
The uptake and digestion of host hemoglobin by malaria parasites during blood-stage growth leads to significant oxidative damage of membrane lipids. Repair of lipid peroxidation damage is crucial for parasite survival. Here, we demonstrate that Plasmodium falciparum imports a host antioxidant enzyme, peroxiredoxin 6 (PRDX6), during hemoglobin uptake from the red blood cell cytosol. PRDX6 is a lipid-peroxidation repair enzyme with phospholipase A (PLA) activity. Inhibition of PRDX6 with a PLA inhibitor, Darapladib, increases lipid-peroxidation damage in the parasite and disrupts transport of hemoglobin-containing vesicles to the food vacuole, causing parasite death. Furthermore, inhibition of PRDX6 synergistically reduces the survival of artemisinin-resistant parasites following co-treatment of parasite cultures with artemisinin and Darapladib. Thus, PRDX6 is a host-derived drug target for development of antimalarial drugs that could help overcome artemisinin resistance.
疟原虫在红内期生长过程中摄取和消化宿主血红蛋白，导致膜脂的严重氧化损伤。脂质过氧化损伤的修复对寄生虫的存活至关重要。在这里，我们证明恶性疟原虫在从红细胞细胞质摄取血红蛋白的过程中会导入一种宿主抗氧化酶——过氧化物酶 6（PRDX6）。PRDX6 是一种具有磷脂酶 A（PLA）活性的脂质过氧化修复酶。用 PLA 抑制剂 Darapladib 抑制 PRDX6 会增加寄生虫中的脂质过氧化损伤，并破坏含血红蛋白囊泡向食物泡的转运，导致寄生虫死亡。此外，在寄生虫培养物中联合使用青蒿素和 Darapladib 治疗时，抑制 PRDX6 会协同降低耐青蒿素寄生虫的存活率。因此，PRDX6 是一种源自宿主的药物靶点，可用于开发抗疟药物，有助于克服青蒿素耐药性。
