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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要困扰消除疟疾工作的众多问题之一是疟疾的出现和传播恶性疟原虫的耐药性。青蒿素耐药导致青蒿素疗效降低联合治疗（ACT）并最终选择对伙伴药物（例如哌喹）的耐药性。显然，多重耐药性疟疾的威胁在今天和以往一样重要，因为宝贵的资源疟疾控制成果受到耐药恶性疟原虫菌株传播潜力的威胁所有目前可用的治疗药物。对青蒿素的耐药性并不是唯一的因素治疗失败。即使在青蒿素耐药性出现之前，复发性感染也很常见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 天单独使用青蒿琥酯治疗会导致约 10% 的复发感染。造成这些现象的根本原因复发性感染归因于青蒿素阻止环生长的独特能力恶性疟原虫的阶段。这些休眠环在恢复和生长之前可以持续数天至数周通常会引起复发感染。我们发布的初步数据使我们得出了这个假设青蒿素抗性的选择是一个两步过程，其中寄生虫的初始反应青蒿素药物压力是一种增强的休眠表型，可提高对药物的耐受性；随后发生赋予耐药性的突变（例如，K13）。在目标 1 中，我们将在我们在独立衍生的青蒿素抗性中发现了新的10号染色体拷贝数变异克隆。目标 2 将使用新型高内涵成像分析来量化增强的休眠恢复青蒿素耐药性与敏感性恶性疟原虫的表型。这些研究的结果将为从青蒿素诱导的休眠中恢复的分子基础提供证据，并可能揭示青蒿素耐药的新机制。