Artemisinin-induced Dormancy & Malaria Treatment Failure

描述（由申请人提供）：疟疾寄生虫抗药性的发展和传播已成为治疗和控制一种每年造成约3亿感染和多达300万死亡的疾病的主要障碍。青蒿素及其衍生物为有效治疗疟疾带来了新的希望。这类药物迅速清除临床症状和寄生虫，包括那些多药耐药性。不幸的是，当这些药物单独使用时，> 40%的病例会产生复发性感染。与其他抗疟疾药物治疗后的复发不同，青蒿素治疗后出现的寄生虫对青蒿素仍然敏感。我们的初步数据表明，恶性疟原虫寄生虫有一种独特的机制来生存青蒿素治疗：药物诱导一个休眠的环阶段寄生虫，其中生长被阻止了几天，然后寄生虫恢复并正常生长。该项目旨在研究在体外用各种青蒿素衍生物治疗后休眠寄生虫的发育和恢复速度。此外，还将估计休眠的持续时间。将在动物模型中研究休眠在体内的作用。将对休眠寄生虫进行生理、细胞和分子表征，以确定休眠的决定因素/标志物，并建立休眠发生的机制。世卫组织强烈建议将青蒿素综合疗法作为减少复发和消除对所有其他廉价、可获得的抗疟药物的广泛耐药性的一项战略。我们将确定联合用药是否能有效杀死休眠寄生虫，或者联合用药的消除半衰期是否是联合治疗成功的关键因素。我们将通过使用恶性疟原虫感染的宿主内动力学的数学模型来补充实验计划，以探索可能影响休眠形成的因素和减少青蒿素治疗后寄生虫复发的潜在方法。 虽然在实地尚未观察到对青蒿素药物的传统耐药性，但所有其他抗疟药物的经验表明，寄生虫对青蒿素药物产生耐药性的风险很大。我们已经在实验室中开发出恶性疟原虫对青蒿素的耐药性，并将描述与耐药性相关的细胞和分子机制。这些包括转录、翻译/翻译后变化和潜在药物转运蛋白的突变。项目的这一部分将阐明寄生虫对这类药物产生抗药性的可能机制以及青蒿素诱导的休眠在这一过程中的作用。 该项目的结果将提供关于青蒿素药物治疗失败机制的宝贵信息。研究结果将有助于制定最佳的ACT方案，改善疟疾患者的治疗效果，并制定预防耐药性发展的战略。

DESCRIPTION (provided by applicant): The development and spread of drug resistance in malaria parasites has become a major obstacle in the treatment and control of a disease that causes approximately 300 million infections and up to 3 million deaths per year. Artemisinin, and its derivatives, offer new hope in the effective treatment of malaria. This class of drugs rapidly clears clinical symptoms and parasites, including those that are multi-drug resistant. Unfortunately, when these drugs are used alone, > 40% of cases will produce recrudescent infections. Unlike recrudescence following treatment by other anti-malarial drugs, parasites appearing after artemisinin treatment remain susceptible to artemisinin. Our preliminary data suggests that P. falciparum parasites have a unique mechanism to survive artemisinin treatment: The drugs induce a dormant ring stage parasite in which growth is arrested for several days before the parasites recover and grow normally. This project aims to investigate the rate at which dormant parasites develop and recover following treatment with various artemisinin derivatives in vitro. In addition the duration of dormancy will be estimated. The role of dormancy in vivo will be investigated in an animal model. Physiological, cellular and molecular characterization of the dormant parasites will be performed to identify determinants/markers for dormancy and establish the mechanism(s) by which dormancy occurs. Artemisinin combination therapy (ACT) has been strongly recommended by WHO as a strategy to reduce recrudescence and to combat widespread resistance to all other cheap, available antimalarial drugs. We will determine if coadministration of drugs is effective in killing dormant parasites, or if the elimination half-life of the combination drug is the key factor in the success of combination therapy. We will supplement the experimental plan by using mathematical models of the in-host dynamics of P. falciparum infections to explore factors that may influence the formation of dormancy and potential ways to reduce parasite recrudescence following treatment with artemisinin. Although conventional resistance to artemisinin drugs has not yet been observed in the field, experiences with all other antimalarial drugs indicate the significant risk of parasites developing resistance to artemisinin drugs. We have developed artemisinin resistance in P. falciparum in our laboratory and will characterize the cellular and molecular mechanism(s) associated with resistance. These include transcriptional, translational/post-translational changes and mutations in potential drug transporters. This component of the project will elucidate possible mechanisms by which parasites develop resistance to this class of drug and the role of artemisinin-induced dormancy in the process. The results of this project will provide valuable information regarding the mechanisms of treatment failure for artemisinin drugs. The results will aid the formulation of optimal ACT regimens, improved treatment outcomes for malaria patients and defined strategies of preventing the development of resistance.