Artemisinin-induced Dormancy & Malaria Treatment Failure

描述(申请人提供)：疟疾寄生虫中耐药性的产生和传播已成为治疗和控制这种每年造成约3亿人感染和多达300万人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。这类药物可以迅速清除临床症状和寄生虫，包括那些具有多重耐药性的药物。不幸的是，当这些药物单独使用时，40%的病例会导致复发感染。与其他抗疟疾药物治疗后复发不同，青蒿素治疗后出现的寄生虫仍然对青蒿素敏感。我们的初步数据表明，恶性疟原虫有一种独特的机制来在青蒿素治疗下存活：药物会诱导一种休眠的环期寄生虫，在这种寄生虫恢复并正常生长之前，这种寄生虫的生长会停止几天。该项目旨在研究休眠寄生虫在体外用不同的青蒿素衍生物治疗后发展和恢复的速度。此外，还将估计休眠的持续时间。休眠在体内的作用将在动物模型中进行研究。将对休眠寄生虫进行生理、细胞和分子特征分析，以确定休眠的决定因素/标记，并建立休眠发生的机制(S)。世卫组织强烈建议将青蒿素联合疗法(ACT)作为减少复发和抗击对所有其他廉价、可获得的抗疟疾药物的广泛耐药性的战略。我们将确定联合给药在杀死休眠寄生虫方面是否有效，或者联合药物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宿主内动态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，以及在青蒿素治疗后减少寄生虫复发的可能方法。 尽管尚未在现场观察到对青蒿素药物的常规耐药性，但所有其他抗疟疾药物的经验表明，寄生虫对青蒿素药物产生抗药性的风险很大。我们在实验室培养了恶性疟原虫对青蒿素的抗性，并将表征与耐药性相关的细胞和分子机制(S)。这些变化包括转录、翻译/翻译后变化以及潜在药物转运蛋白的突变。该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。 该项目的结果将为青蒿素类药物治疗失败的机制提供有价值的信息。这些结果将有助于制定最佳的ACT方案，改善疟疾患者的治疗结果，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.