Elucidating mechanisms for artemisinin-induced dormancy in Plasmodium falciparum

阐明青蒿素诱导恶性疟原虫休眠的机制

• 批准号: 10742385
• 负责人: DENNIS E KYLE
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742385
• 关键词: Antimalarials; Artemisinins; Bacteria; Biological Assay; CRISPR/Cas technology; Candidate Disease Gene; Cells; Chromosome 10; Chromosome 13; Circulation; Clinical; Combined Modality Therapy; Complex; Copy Number Polymorphism; Culicidae; Data; Development; Drug Exposure; Drug resistance; Erythrocytes; Exhibits; Exposure to; Gene Amplification; Genes; Growth; Half-Life; Image; In Vitro; Infection; Investigation; Laboratories; Link; Malaria; Malignant Neoplasms; Methods; Molecular; Multi-Drug Resistance; Mutation; Parasites; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiologic pulse; Plasmids; Plasmodium falciparum; Predisposition; Probability; Process; Publishing; Recovery; Refractory; Resistance; Resistance development; Role; Survival Rate; Testing; Treatment Failure; Tuberculosis; Work; artesunate; burden of illness; clinically relevant; drug discovery; effective therapy; enhancer-binding protein AP-2; imaging modality; novel; overexpression; pressure; prevent; resistance mechanism; resistant Plasmodium falciparum; resistant strain; response; transmission process; treatment duration

Project Summary Among the numerous problems plaguing the malaria elimination efforts is the emergence and spread of drug resistance in P. falciparum. Resistance to artemisinin has led to reduced efficacy of artemisinin combination therapy (ACTs) and ultimately selection of resistance to the partner drugs (e.g., piperaquine). Clearly the threat of multi-drug resistant malaria is as important today as it has ever been, with the precious gains in malaria control threatened by the potential for the spread of P. falciparum strains that are resistant to all currently available treatment drugs. Resistance to artemisinin is not the only factor responsible for treatment failures. Even before artemisinin resistance emerged, recrudescent infections were commonly observed when patients were treated with artemisinin derivatives alone. In some studies, even 5-7 days of treatment with artesunate alone led to ~10% recrudescent infections. The underlying cause of these recrudescent infections has been attributed to the unique ability of artemisinin to arrest the growth of ring stages of P. falciparum. These dormant rings can persist for days to weeks before recovering and growing normally to cause a recrudescent infection. Our published and preliminary data led us to the hypothesis that selection of artemisinin resistance is a two-step process in which the initial responses of the parasite to artemisinin drug pressure is an enhanced dormancy phenotype that confers increased tolerance to drug; subsequently resistance conferring mutations occur (e.g., K13). In Aim 1 we will overexpress genes in a novel chromosome 10 copy number variant we identified in independently derived artemisinin-resistant clones. In Aim 2 will use novel high content imaging assays to quantify enhanced dormancy recovery phenotypes in artemisinin-resistant versus -susceptible P. falciparum. The results of these studies will provide evidence for the molecular basis of recovery from artemisinin-induced dormancy and possibly reveal new mechanisms of resistance to artemisinin.

项目摘要 在消灭疟疾努力中遇到的众多问题中， 恶性疟原虫的耐药性对青蒿素的耐药性导致青蒿素疗效降低 联合治疗（ACT）和最终选择对伴侣药物的抗性（例如，哌喹）。 显然，耐多药疟疾的威胁今天和以往一样重要， 疟疾控制方面取得的进展受到恶性疟原虫耐药菌株传播的威胁 所有现有的治疗药物。对青蒿素的耐药性并不是导致 治疗失败。即使在青蒿素耐药性出现之前， 当患者单独接受青蒿素衍生物治疗时观察到。在一些研究中，甚至5-7天的 单独使用青蒿琥酯治疗导致约10%的复发感染。这些问题的根本原因 复发性感染被归因于青蒿素阻止环生长的独特能力。 恶性疟原虫阶段。这些休眠的年轮在恢复和生长之前可以持续几天到几周 通常会导致复发性感染我们发表的和初步的数据使我们得出了这样的假设 青蒿素抗性的选择是一个两步过程， 青蒿素药物压力是一种增强的休眠表型，赋予药物耐受性增加; 随后发生赋予抗性的突变（例如，K13）。在Aim 1中，我们将在一个 新的染色体10拷贝数变异，我们在独立来源的青蒿素耐药 克隆在目标2将使用新的高内容成像分析，以量化增强休眠恢复 青蒿素抗性与敏感性恶性疟原虫的表型。这些研究的结果将 为青蒿素诱导休眠恢复的分子基础提供了证据， 揭示青蒿素耐药的新机制。