Unité de Paludologie, Institut Pasteur Côte d'Ivoire, 01 BP 490, Abidjan 01, Côte d'Ivoire.
Laboratoire Biologie et Santé, Université Felix Houphouët Boigny, Abidjan, Côte d'Ivoire.
Malar J. 2024 Jan 4;23(1):9. doi: 10.1186/s12936-023-04819-5.
Decreased efficacy of artemisinin-based combination therapy (ACT) for Plasmodium falciparum malaria has been previously reported in patients with sickle cell disease (SCD). The main purpose of this study was to investigate the in vitro susceptibility of isolates to dihydro-artemisinin (DHA) to provide a hypothesis to explain this treatment failure.
Isolates were collected from patients attending health centres in Abidjan with uncomplicated P. falciparum malaria. The haemoglobin type has been identified and in vitro drug sensitivity tests were conducted with the ring stage assay and maturation inhibition assay.
134 isolates were obtained. Parasitaemia and haemoglobin levels at inclusion were lower in patients with haemoglobin HbSS and HbSC than in patients with normal HbAA. After ex vivo RSA and drug inhibition assays, the lowest rate of parasitic growth was found with isolates from HbAS red cells. Conversely, a significantly higher survival rate of parasites ranging from 15 to 34% were observed in isolates from HbSS. Isolates with in vitro reduced DHA sensitivity correlate with lower RBC count and haematocrit and higher parasitaemia at inclusion compared to those with isolates with normal DHA sensitivity. However, this decrease of in vitro sensitivity to DHA was not associated with Kelch 13-Propeller gene polymorphism.
This study highlights an in vitro decreased sensitivity to DHA, for isolates collected from HbSS patients, not related to the Pfkelch13 gene mutations. These results are in line with recent studies pointing out the role of the redox context in the efficacy of the drug. Indeed, SCD red cells harbour a highly different ionic and redox context in comparison with normal red cells. This study offers new insights into the understanding of artemisinin selective pressure on the malaria parasite in the context of haemoglobinopathies in Africa.
先前有报道称，镰状细胞病（SCD）患者青蒿素为基础的联合疗法（ACT）治疗效果降低。本研究的主要目的是研究分离株对二氢青蒿素（DHA）的体外敏感性，为解释这种治疗失败提供假设。
从阿比让的卫生中心就诊的患有无并发症恶性疟原虫疟疾的患者中采集分离株。已鉴定了血红蛋白类型，并通过环阶段测定法和成熟抑制测定法进行了体外药物敏感性测试。
共获得 134 个分离株。与正常 HbAA 患者相比，HbSS 和 HbSC 患者的寄生虫血症和血红蛋白水平在纳入时较低。经过体外 RSA 和药物抑制测定后，在 HbAS 红细胞的分离株中发现了最低的寄生虫生长率。相反，在 HbSS 的分离株中观察到寄生虫存活率明显更高，范围为 15%至 34%。与体外 DHA 敏感性正常的分离株相比，体外 DHA 敏感性降低的分离株与较低的 RBC 计数和血细胞比容以及纳入时较高的寄生虫血症相关。然而，这种对 DHA 的体外敏感性降低与 Kelch 13-Propeller 基因多态性无关。
本研究强调了从 HbSS 患者中分离的分离株对 DHA 的体外敏感性降低，与 Pfkelch13 基因突变无关。这些结果与最近的研究一致，这些研究指出了氧化还原环境在药物疗效中的作用。实际上，与正常红细胞相比，SCD 红细胞具有高度不同的离子和氧化还原环境。本研究为理解在非洲血红蛋白病背景下青蒿素对疟原虫的选择性压力提供了新的见解。
