Pathogenesis & Antivirals for Noroviruses

项目总结 人类诺如病毒(HuNov)是美国和全球胃肠炎的主要原因。这个 与这种病原体相关的重大公共卫生负担刺激了疫苗开发和 在抗病毒药物的评估中。然而，关于病毒发病机制的一些根本性的重要问题 保护性免疫反应仍然没有得到回答，解决这些挑战对于 制定有效的策略预防和治疗人间新城疫病毒感染。 在这个项目中，我们的目标是：(I)阐明与人类新城疫病毒相关的临床表现的中介因素 胃肠炎；(Ii)开发病毒蛋白水解酶和聚合酶类药物抑制剂并进行临床前试验，如 潜在的抗病毒药物；以及(Iii)确定人类免疫系统在 并确定与病毒中和和保护性免疫相关的表位。 使用临床数据和先前人类实验挑战研究的样本，以及传染性 人类肠类病毒(HIE)的检测使我们能够对HuNov进行功能性和机械性的研究 致病机理和病毒中和。HIE培养系统也第一次允许我们直接 评估抗病毒药物。因此，这个项目的发现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点。类药物抑制剂 将优先通过合理的药物设计和药物化学来评估它们对抑制 病毒以及与感染和疾病相关的关键因素。最后，对抗体谱系的鉴定 与保护性免疫和病毒中和相关将为疫苗设计和测试提供信息。加在一起，这些 研究将实现功能性、机械性和翻译性的贡献，从而减轻公共卫生负担 新城疫病毒引起的胃肠炎。 。

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. .