Artemisinin-induced Dormancy & Malaria Treatment Failure

疟疾寄生虫耐药性的发展和传播已成为疟疾治疗和治疗的主要障碍。 控制每年造成约3亿人感染和多达300万人死亡的疾病。青蒿素， 及其衍生物，为疟疾的有效治疗带来了新的希望。这类药物迅速清除了临床 症状和寄生虫，包括那些多药耐药的。不幸的是，当这些药物单独使用时，&gt； 40%的病例会产生复发感染。与其他抗疟疾药物治疗后复发不同 青蒿素治疗后出现的药物、寄生虫仍然对青蒿素敏感。我们的初步数据显示 恶性疟原虫对存活素治疗有独特的作用机制。这些药物引起了一种休眠 寄生虫的阶段性寄生虫，在寄生虫恢复并正常生长之前，生长会停止几天。这个项目 目的是调查不同青蒿素治疗后休眠寄生虫的发展和恢复的速度 体外衍生品。此外，还将估计休眠的持续时间。休眠在体内的作用将是 在动物模型中进行了研究。休眠寄生虫的生理、细胞和分子特征将是 以确定休眠的决定因素/标记，并建立休眠发生的机制(S)。 青蒿素联合疗法(ACT)已被世界卫生组织强烈推荐为减少复发的一种策略 并与所有其他廉价、可获得的抗疟疾药物的普遍耐药性作斗争。我们将确定是否联合- 给药在杀死休眠寄生虫方面是有效的，或者如果联合药物的消除半衰期是 综合治疗成功的关键因素。我们将用数学方法来补充实验计划 恶性疟原虫感染宿主动态模型探讨可能影响恶性疟原虫形成的因素 青蒿素治疗后的休眠和减少寄生虫复发的可能方法。 尽管在现场还没有观察到青蒿素药物的常规耐药性，但所有其他药物的经验 抗疟疾药物表明寄生虫对青蒿素药物产生抗药性的风险很大。我们有 恶性疟原虫对青蒿素的抗药性研究 与抗性有关的机制(S)。这些变化包括转录、翻译/翻译后变化和 潜在药物转运体的突变。项目的这一组成部分将阐明可能的机制，通过这些机制 寄生虫对这类药物产生抗药性，并在此过程中发挥青蒿素诱导的休眠作用。 该项目的结果将提供有关治疗失败机制的有价值的信息。 青蒿素类药物。这一结果将有助于制定最佳的ACT方案，改善 疟疾患者和明确的防止抗药性发展的战略。

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 infectionsand up to 3 million deaths per year. Artemisinin, and it's derivatives, offer new hope in the effective treatment of malaria.This class of drugs rapidly clears clinical symptoms and parasites, includingthose 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 artemisinintreatment remain susceptible to artemisinin. Our preliminary data suggests that P. falciparum parasites have a unique mechanismto surviveartemisinintreatment:. The drugs induce a dormantring 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 followingtreatment 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 antimalarialdrugs. We will determine if co- administration 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 combinationtherapy. We will supplementthe experimental plan by using mathematical models of the in-host dynamics of P. falciparum infectionsto explore factors that may influence the formation of dormancy and potential ways to reduce parasite recrudescence following treatment withartemisinin. Although conventional resistance to artemisinindrugs 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 artemisininresistance in P. falciparum in our laboratory and will characterize the cellular andmolecular 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 informationregarding 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 developmentof resistance.