Elucidating host phosphosignaling regulation of Plasmodium vivax liver stage

阐明间日疟原虫肝脏阶段的宿主磷酸信号调节

• 批准号: 10056490
• 负责人: Alexis Kaushansky
• 金额: $ 28.18万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-22 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056490
• 关键词: Antibodies; Cell physiology; Cells; Collaborations; Data; Detection; Development; Disease; Disease model; Drug Targeting; Ensure; Event; Goals; Health; Hepatocyte; Host Defense; Human; Individual; Infection; Integration Host Factors; Intervention; Knowledge; Laboratories; Lead; Liver; Machine Learning; Malaria; Measures; Methodology; Monitor; Morbidity - disease rate; Mus; Oligonucleotides; Onset of illness; Parasites; Pathway Analysis; Pharmaceutical Preparations; Phenotype; Phosphoproteins; Phosphorylation; Phosphotransferases; Plasmodium; Plasmodium vivax; Plasmodium yoelii; Play; Prevalence; Process; Production; Property; Proteins; Recording of previous events; Regulation; Regulatory Pathway; Relapse; Research Personnel; Rodent; Role; Sampling; Signal Transduction; Sporozoites; Symptoms; System; Testing; Toxic effect; Universities; Variant; Vivax Malaria; base; differential expression; digital; experimental study; in vivo; infection rate; inhibitor/antagonist; insight; kinase inhibitor; knock-down; liver infection; malaria infection; mortality; novel; novel strategies; pathogen; side effect; small hairpin RNA; small molecule

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.

抽象的 尽管在过去的一个世纪中做出了重大根除努力，疟疾仍然是世界范围内的一个重大健康负担。 间日疟原虫因其形成休眠阶段的能力而成为根除疟疾的最大障碍 在肝脏内，称为休眠子。休眠子可以在初次感染后数周至数年重新激活，导致 复发，并且只能通过两种具有广泛副作用和毒性的许可药物来靶向，这限制了 他们的用途。疾病流行模型表明，即使催眠体丰度略有减少， 肝脏可能对疾病的传播产生重大影响。所有已感染的疟原虫寄生虫 广泛的研究表明，其入侵和发育依赖于特定的宿主信号事件 通过肝期感染。这些宿主因素代表了基于宿主的干预措施的潜在目标。 不幸的是，对于允许间日疟原虫传播的宿主因素仍然缺乏了解。 肝脏阶段得以持续和发展，很大程度上是因为与生长相关的技术挑战 寄生虫，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 通过使用激酶回归和数字空间分析两种方法来询问宿主驱动的挑战 间日疟原虫感染的肝细胞中的磷酸信号传导，包括那些含有休眠子的肝细胞。如果成功的话，我们的 该方法还将鉴定间日疟原虫发育和休眠肝脏阶段所必需的宿主激酶 作为因感染而改变的磷酸信号传导。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，并在此过程中提供对细胞的深入了解 促进肝期寄生虫发育和休眠的生态位。除了增强 了解这个很大程度上神秘的过程后，这些信息可以为宿主定向治疗提供信息，这 代表了一种针对休眠疟疾寄生虫的新方法。