Exploiting Fatty Acid Metabolism To Cure Malaria

描述（由申请人提供）：基于青蒿素的联合疗法在对抗恶性疟原虫疟疾方面取得了成功，激发了人们呼吁根除这种毁灭性的寄生虫病。然而，新出现的青蒿素耐药性报告以及替代一线药物的缺乏凸显了对新控制方法的迫切需要。我们提出了一项大胆的新计划，利用多学科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个特定生化途径。目前大多数可用的抗疟药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，而许多疫苗工作都集中在基于重组亚基的方法上。基于我们最近的发现，即肝脏阶段和血液阶段寄生虫的脂肪酸生物学存在根本差异，我们提出了一种完全不同的方法。在啮齿类寄生虫伯氏疟原虫中，参与 II 型脂肪酸从头合成 (FAS-II) 的 fabI 基因的缺失对血液阶段寄生虫的生长没有可测量的影响，表明该阶段依赖于宿主脂肪酸的输入和修饰以进行细胞内复制。相比之下，fabI 基因的破坏严重损害了肝脏阶段寄生虫完成其发育并启动血液阶段感染的能力。在相关的啮齿动物 P. yoelii 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。这些减毒寄生虫引发了针对传染性寄生虫挑战的强大保护性免疫力。基于这些发现，我们假设可以独特地利用寄生虫阶段特异性脂肪酸代谢差异来开发有效的抗疟疫苗和药物。我们将实施一种系统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完全停滞，并引发强大且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疫苗，以与 Sanaria 合作启动临床前评估。我们还定义了一种实验方法来评估葛兰素史克 (GlaxoSmithKline) 提供的一组 FAS-II 抑制剂在体外和体内阻断肝阶段发育的能力。如果找到有效且药理学上合适的抑制剂，将在灵长类疟疾预防模型中对其进行评估。最后，我们对无性血液阶段复制过程中宿主脂肪酸的输入和修饰的寄生虫机制的研究将验证关键效应器，并指导开发治疗剂的筛选，通过使疟原虫血液阶段缺乏必需的宿主营养来杀死疟原虫血液阶段。这个“高风险/高回报”项目基于学术团体和行业合作伙伴之间的协作努力，可以快速将实验发现转化为临床前评估。该项目成功发现了新的介入工具，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. )