Exploiting Fatty Acid Metabolism To Cure Malaria

描述（由申请人提供）：以青蒿素为基础的联合疗法在防治恶性疟原虫疟疾方面取得的成功激发了根除这种毁灭性寄生虫疾病的呼声。然而，关于出现青蒿素耐药性的新报告，以及缺乏替代一线药物，突出表明迫切需要新的控制方法。我们提出了一个大胆的新计划，利用多学科合作方法开发新一代抗疟疾疫苗和药物，以利用寄生虫生命周期中的一个特定生化途径。目前大多数可用的抗疟药物针对的是有症状的血液阶段寄生虫，而不是最初的无症状肝脏阶段寄生虫，而许多疫苗工作的重点是基于亚单位的重组方法。基于我们最近的发现，我们提出了一种完全不同的方法，肝脏和血液阶段的寄生虫在脂肪酸生物学上有根本的不同。在啮齿动物伯氏疟原虫中，fabI基因的缺失对血期寄生虫生长没有明显的影响，该基因参与了新生II型脂肪酸合成（FAS-II），这表明血期寄生虫的生长依赖于宿主脂肪酸的输入和修饰，以进行细胞内复制。相反，fabI基因的破坏严重损害了肝期寄生虫完成发育和启动血期感染的能力。在相关的啮齿动物种P. yoelii中，FAS-II基因fabB/F的缺失产生了从未完成肝脏发育的寄生虫。这些减毒的寄生虫对感染性寄生虫的攻击产生了强大的保护性免疫。基于这些发现，我们假设可以独特地利用寄生虫在脂肪酸代谢方面的阶段特异性差异来开发有效的抗疟疾疫苗和药物。我们将实施一种系统的方法来识别参与脂肪酸代谢和相关过程的基因组合，当这些基因被删除时，可以导致寄生虫肝脏阶段发育的完全停止，并引发一种强大的、完全保护性的免疫反应。与Sanaria合作，成功的伯氏疟原虫疫苗将转化为恶性疟原虫，以启动临床前评估。我们还定义了一种实验方法来评估一组来自葛兰素史克（GlaxoSmithKline）的FAS-II抑制剂，它们在体外和体内阻断肝脏阶段发展的能力。如果发现有效和药理学上合适的抑制剂，这些将在灵长类动物疟疾预防模型中进行评估。最后，我们对寄生虫在无性血期复制过程中输入和修饰宿主脂肪酸的机制的研究将验证关键效应物，并指导筛选通过饥饿宿主必需营养物质来杀死疟原虫血期的治疗药物。这个“高风险/高回报”的项目是基于学术团体和行业伙伴之间的合作努力，可以迅速将实验发现转化为临床前评估。这个项目所产生的新干预工具的成功发现具有从根本上改变疟疾预防和控制方式的令人兴奋的潜力。

DESCRIPTION (provided by applicant): The success of artemisinin-based combination therapies in combating Plasmodium falciparum malaria has inspired calls for the eradication of this devastating parasitic disease. However, new reports of emerging artemisinin resistance, and the absence of alternative first-line drugs, highlight an urgent need for new control methods. We propose a bold new plan to develop a new generation of antimalarial vaccines and drugs using a multidisciplinary, collaborative approach to exploit one particular biochemical pathway in the parasite lifecycle. Most currently available antimalarials target the symptomatic blood stage parasites rather than the initial asymptomatic liver stage, while many vaccine efforts have focused on recombinant subunit-based approaches. We are proposing a completely different approach based on our recent discovery that liver and blood stage parasites differ fundamentally in their fatty acid biology. In the rodent parasite P. berghei, deletion of the fabI gene, involved in de novo type II fatty acid synthesis (FAS-II), had no measurable effect on blood stage parasite growth, indicating that this stage depends on the import and modification of host fatty acids for intracellular replication. In contrast, the disruption of the fabI gene severely compromised the ability of the liver stage parasites to complete their development and initiate blood stage infection. In the related rodent species P. yoelii, deletion of the FAS-II gene fabB/F produced parasites that never completed their liver stage development. These attenuated parasites elicited robust protective immunity against infectious parasite challenge. Based on these findings, we hypothesize that parasite stage-specific differences in fatty acid metabolism can be uniquely exploited to develop effective antimalarial vaccines and drugs. We will implement a systematic approach to identifying combinations of genes involved in fatty acid metabolism and related processes, which when deleted can cause a total arrest of parasite liver stage development and elicit a robust and fully protective immune response. Successful P. berghei vaccines will be translated into P. falciparum to initiate preclinical assessments, in collaboration with Sanaria. We also define an experimental approach to evaluate a panel of FAS-II inhibitors, available from GlaxoSmithKline, for their ability to block liver stage development in vitro and in vivo. If potent and pharmacologically suitable inhibitors are found, these will be evaluated in a primate malaria prophylaxis model. Finally, our investigations of parasite mechanisms of import and modification of host fatty acids during asexual blood stage replication will validate the key effectors and guide the development of screens for curative agents that kill Plasmodium blood stages by starving them of essential host nutrients. This "high risk/high reward" project is based on a collaborative effort between academic groups and industry partners that can rapidly translate experimental discoveries into preclinical assessment. The successful discovery of new interventional tools arising from this project has the exciting potential to fundamentally transform the way in which malaria is prevented and controlled. )