Pathogenesis & Antivirals for Noroviruses

项目摘要 人类诺如病毒（HuNoV）是美国和全球胃肠炎的主要原因。的 与该病原体相关的重大公共卫生负担刺激了疫苗开发的努力， 抗病毒药物的评估。然而，关于病毒致病机理的一些根本性的重要问题 和保护性免疫反应仍然没有得到解决，解决这些挑战对于 开发预防和治疗HuNoV感染的有效策略。 在这个项目中，我们的目标是：（i）阐明介导与HuNoV相关的临床表现的因素 （ii）开发和临床前测试病毒蛋白酶和聚合酶的药物样抑制剂， 潜在的抗病毒剂;和（iii）确定在治疗期间由人免疫系统识别的HuNoV表位。 感染和鉴定与病毒中和和保护性免疫相关表位。 使用来自先前人体实验挑战研究的临床数据和样本，以及感染性 在人肠类肠（HIE）中的测定允许我们对HuNoV进行功能和机制研究， 致病性和病毒中和。HIE培养系统也首次允许我们直接 评估抗病毒药物因此，本项目的研究结果将提供对这些机制的新理解 并确定可用于治疗疾病症状的潜在靶标。类药物抑制剂 通过合理的药物设计和药物化学优先考虑，将评价其对抑制 病毒和与感染和疾病相关的关键因素。最后，鉴定抗体库， 与保护性免疫相关，病毒中和将为疫苗设计和测试提供信息。所有这些 研究将使功能，机制和翻译的贡献，将减少公共卫生负担 病毒性胃肠炎 .

PROJECT SUMMARY Human noroviruses (HuNoVs) are a leading causes of gastroenteritis in the United States and globally. The significant public health burden associated with this pathogen has stimulated efforts in vaccine development and in the evaluation of antivirals. However, a number of fundamentally important questions on virus pathogenesis and protective immune responses remain unanswered and addressing these challenges is critical for the development of effective strategies to prevent and treat HuNoV infections. In this project, we aim to: (i) Elucidate factors that mediate clinical presentations associated with HuNoV gastroenteritis; (ii) Develop and pre-clinically test drug-like inhibitors of virus protease and polymerase as potential antiviral agents; and (iii) Determine HuNoV epitopes recognized by the human immune system during infection and identify epitopes associated with virus neutralization and protective immunity. Using clinical data and samples from previous human experimental challenge studies, together with infectivity assays in human intestinal enteroids (HIEs) allows us to carry out functional and mechanistic on HuNoV pathogenesis and virus neutralization. The HIE cultivation system also, for the first time, allows us to directly evaluate antivirals. The findings from this project will therefore provide new understanding of the mechanisms of HuNoV disease and identify potential targets that can used to treat disease symptoms. Drug-like inhibitors prioritized through rational drug design and medicinal chemistry will be evaluated for their effects on inhibition of virus and key factors associated with infection and disease. Finally, identification of antibody repertoires that correlate with protective immunity and virus neutralization will inform vaccine design and testing. Together, these studies will enable functional, mechanistic and translational contributions that will reduce the public health burden of HuNoV gastroenteritis. .