Exploiting Fatty Acid Metabolism To Cure Malaria

描述（由申请人提供）：青蒿素类复方疗法在防治恶性疟原虫疟疾方面的成功激发了根除这种毁灭性寄生虫病的呼声。然而，关于青蒿素耐药性的新报告以及缺乏替代一线药物的情况突出表明，迫切需要新的控制方法。我们提出了一个大胆的新计划，利用多学科的协作方法开发新一代抗疟疫苗和药物，以利用寄生虫生命周期中的一种特定生化途径。大多数目前可用的抗疟药针对有症状的血液阶段寄生虫，而不是最初的无症状的肝脏阶段，而许多疫苗的努力集中在重组亚基为基础的方法。我们提出了一种完全不同的方法，基于我们最近的发现，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。在啮齿动物寄生虫伯氏疟原虫中，fabI基因的缺失，参与从头II型脂肪酸合成（FAS-II），对血液阶段寄生虫的生长没有可测量的影响，表明这个阶段依赖于宿主脂肪酸的进口和修饰进行细胞内复制。相反，fabI基因的破坏严重损害了肝脏阶段寄生虫完成其发育和启动血液阶段感染的能力。在相关的啮齿类物种约氏疟原虫中，FAS-II基因fabB/F的缺失产生了从未完成肝脏阶段发育的寄生虫。这些减毒的寄生虫引起了强大的保护性免疫对感染性寄生虫的挑战。基于这些发现，我们假设寄生虫阶段特异性脂肪酸代谢差异可以被独特地利用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，这些基因在删除时可以导致寄生虫肝脏阶段发育的完全停滞，并引发强大和完全保护性的免疫反应。成功的伯氏疟原虫疫苗将被转化为恶性疟原虫，以启动临床前评估，与Sanaria合作。我们还定义了一种实验方法来评估一组FAS-II抑制剂，可从葛兰素史克公司，他们的能力，阻止肝脏阶段的发展在体外和体内。如果发现有效的和可耐受的抑制剂，这些将在灵长类动物疟疾预防模型中进行评估。最后，我们的调查的寄生虫机制的进口和修改的宿主脂肪酸在无性血液阶段复制将验证关键的效应和指导屏幕的发展，杀死疟原虫血液阶段的治疗剂，饥饿他们的必需的宿主营养素。这个“高风险/高回报”项目是基于学术团体和行业合作伙伴之间的合作努力，可以快速将实验发现转化为临床前评估。从该项目中成功发现新的干预工具，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. )