Elucidating host phosphosignaling regulation of Plasmodium vivax liver stage

摘要 尽管在过去的一个世纪里做出了重大的根除努力，但疟疾仍然是世界范围内的重大健康负担。 间日疟原虫由于能够形成休眠阶段而成为根除疟疾的最大障碍。 在肝脏内，被称为催眠药。催眠虫可以在最初感染几周到几年后重新激活，导致 复发，并且只能被两种具有广泛副作用和毒性的特许药物靶向限制 它们的用途。疾病流行模型表明，即使催眠药丰度略有下降， 肝脏可能对疾病的传播产生重大影响。所有被感染的疟原虫 广泛研究表明，入侵和发育依赖于特定的宿主信号事件 通过肝期感染。这些宿主因素是以宿主为基础的干预措施的潜在目标。 不幸的是，关于允许间日疟原虫传播的宿主因素仍然缺乏知识。 肝脏阶段的持续和发展，很大程度上是因为与生长相关的技术挑战 寄生，然后监测罕见感染细胞中的宿主信号事件。在这里，我们建议克服这些 用两种方法-的挑战 间日疟原虫感染的肝细胞中的磷信号，包括那些含有催眠虫的肝细胞。如果成功，我们的 该方法将确定间日疟原虫发育和休眠肝脏阶段所必需的宿主激酶。 作为被感染改变的磷信号。这些数据将极大地增强我们对 调节间日疟原虫肝脏感染的宿主因素，并通过这样做提供了对细胞 促进肝期寄生虫发育和休眠的生态位。除了增强 对这一神秘过程的理解，这一信息可能会为宿主指导的治疗提供信息， 代表了一种针对休眠疟疾寄生虫的新方法。

ABSTRACT Despite major eradication efforts over the past century, malaria remains a significant world-wide health burden. Plasmodium vivax poses the greatest obstacle to malaria eradication due to its ability to form dormant stages within the liver, called hypnozoites. Hypnozoites can reactivate weeks to years after the initial infection, leading to relapses, and can only be targeted by two licensed drugs with extensive side effects and toxicity that limits their use. Models of disease prevalence suggest that even a modest reduction of hypnozoite abundance in the liver could make a major impact on the spread of disease. All Plasmodium parasites that have been extensively studied have been shown to rely on specific host signaling events for invasion and development through liver stage infection. These host factors represent potential targets for host-based interventions. Unfortunately, there remains a dearth of knowledge regarding the host factors that permit Plasmodium vivax liver stages to persist and develop, in large part because of technical challenges associated with growing the parasite and then monitoring host signaling events in rare infected cells. Here, we propose to overcome these challenges by using two approaches, kinase regression and digital spatial profiling, to interrogate host-driven phosphosignaling in P. vivax-infected hepatocytes, including those that harbor hypnozoites. If successful, our approach will identify host kinases that are necessary for P. vivax developing and dormant liver stages, as well as phosphosignaling that is altered by infection. These data will dramatically enhance our understanding of host factors that regulate Plasmodium vivax liver infection, and in doing so provide insight into the cellular niche that promotes liver-stage parasite development and dormancy. In addition to enhancing the understanding of this largely mysterious process, this information could inform host-directed therapies, which represent a novel approach to targeting dormant malaria parasites.