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.

项目摘要困扰疟疾消除工作的许多问题是出现和传播恶性疟原虫的耐药性。对青蒿素的耐药性导致青蒿素的疗效降低联合疗法（ACTS）以及最终选择对伴侣药物的抗性（例如，piperaquine）。显然，今天的多药耐药疟疾的威胁与以往一样重要，珍贵疟疾控制的收益受到抗性恶性疟原虫菌株的蔓延的威胁目前所有可用的治疗药物。对青蒿素的抵抗并不是唯一负责的因素治疗失败。甚至在出现青蒿素耐药性之前，通常都是观察到单独用青蒿素衍生物治疗患者时观察到。在某些研究中，即使是5-7天单独使用敏捷的治疗导致〜10％的复发感染。这些的根本原因重新感染的归因于阿甘米辛素阻止环的独特能力恶性疟原虫的阶段。这些休眠环可以持续数天到几周，然后恢复和增长通常会引起重新感染。我们发布的初步数据使我们提出了假设青蒿素耐药性的选择是一个两步的过程，其中寄生虫的初始反应对于青蒿素药物压力是一种增强的休眠表型，赋予对药物的耐受性的增加。随后发生抗性赋予突变（例如K13）。在AIM 1中，我们将过表达基因我们在独立衍生的青蒿素耐药的10个拷贝数变体的新型染色体数字变体克隆。在AIM 2中将使用新颖的高内容成像测定法来量化增强的休眠恢复青蒿素抗性与敏感的恶性假单胞菌中的表型。这些研究的结果将提供从青蒿素诱导的休眠和可能的分子恢复分子基础的证据揭示对青蒿素抗性的新机制。