Susceptibility and Protective Immunity to Noroviruses

描述（由申请方提供）：诺如病毒是全球食源性胃肠炎的最重要原因，在美国，约85-96%的急性非细菌性胃肠炎暴发是由诺如病毒引起的。被称为“胃流感”，退休社区爆发是普遍的，可导致1-2%的老年人死亡率。根据衣壳序列将诺如病毒分为5个基因组。基因组I（GI）和II（GII）几乎占所有人类感染。每个基因组进一步分为基因型。GII.4基因型是全世界所有诺如病毒暴发的70-80%的病原体。诺如病毒主要衣壳蛋白形成二十面体壳，含有主要抗原决定簇，并与组织相容性组抗原（HBGA）碳水化合物（假定的进入受体）相互作用。本研究探讨了诺如病毒衣壳进化、结构和HBGA识别的分子机制，这些机制是免疫驱动的抗原漂移和欺骗性印迹的函数。我们确定了替代菌株随时间演变的机制，识别新的HBGA碳水化合物结合靶点，并逃避高度渗透的宿主易感性等位基因和保护性群体免疫。在定义突变、抗原变异、免疫原性、欺骗性印迹、结构和HGBA结合之间的关系的同时，我们的跨学科团队同时在猪中开发了一个强大的GII.4挑战模型，并表征了针对GI和GII菌株的人单克隆抗体（mAb），为推进该领域提供了关键试剂。公共卫生相关性：诺如病毒是全世界食源性胃肠炎的最重要原因，在美国，约85-96%的急性非细菌性胃肠炎的选定爆发是由诺如病毒引起的。诺如病毒通过摄入粪便污染的食物和水、接触污染的表面、雾化呕吐物和直接人与人接触传播。诺如病毒的巨大公共卫生意义由美国估计约23，000，000例感染、50，000例住院和310例死亡病例证明。在发展中国家，反复感染可能导致婴幼儿营养不良，并可能导致死亡。该提案测试了诺如病毒株随时间进化以使用不同的细胞受体并避免宿主免疫监视的假设。如果这个模型是正确的，那么可以制定长期的菌株特异性保护性免疫和免疫预防，以防止当代菌株感染，提供急需的针对这种重要的人类病原体的疫苗接种策略。

DESCRIPTION (provided by applicant): Noroviruses are the most important cause of food-borne gastroenteritis worldwide and cause ~85-96% of selected outbreaks of acute non-bacterial gastroenteritis in the US. Heralded as the "stomach flu", retirement community outbreaks are pervasive and can result in 1-2% mortality rates in the elderly. Based on capsid sequences norovirus are divided into 5 genogroups. Genogroup I (GI) and II (GII) account for almost all human infections. Each genogroup is further divided into genotypes. The GII.4 genotype is the causative agent of 70-80% of all norovirus outbreaks worldwide. The norovirus major capsid protein forms an icosohedral shell, contains major antigenic determinants and interacts with histoblood group antigen (HBGA) carbohydrates, putative receptors for entry. This study investigates the molecular mechanisms governing norovirus capsid evolution, structure and HBGA recognition as a function of immune driven antigenic drift and deceptive imprinting. We identify the mechanisms by which replacement strains evolve over time, recognize new HBGA carbohydrate binding targets, and escape from highly penetrent host susceptibility alleles and protective herd immunity. While defining the relationships between mutation, antigenic variation, immunogenicity, deceptive imprinting, structure and HGBA binding, our interdisciplinary team simultaneously develops a robust GII.4 challenge model in swine and characterizes human monoclonal antibodies (mAb) to GI and GII strains, providing key reagents for advancing the field. PUBLIC HEALTH RELEVANCE: for Noro grant Noroviruses are the most important cause of food-borne gastroenteritis worldwide and cause ~85-96% of selected outbreaks of acute non-bacterial gastroenteritis in the US. Noroviruses are transmitted via ingestion of fecally contaminated food and water, exposure to contaminated surfaces, aerosolized vomitus and direct person-to-person contact. The tremendous public health significance of norovirus is evidenced by the estimated ~23,000,000 infections, 50,000 hospitalizations, and 310 fatal cases in the US. In developing nations, repeat infection likely contribute to malnutrition in infants and young children and may result in death. This proposal tests the hypothesis that Norovirus strains evolve over time to use varying cellular receptors and avoid host immune surveillance. If this model is correct, then long-term strain specific protective immunity and immune prophylaxis can be formulated to protect against contemporary strain infections providing a much needed vaccination strategy against this important human pathogen.