Host Genetic Susceptibility and Immune Responses to Norovirus Infections

描述（由申请方提供）：诺如病毒（NoV）是全球食源性疾病和急性非细菌性胃肠炎的最常见原因。细胞培养和动物模型的缺乏阻碍了对宿主易感性和宿主-病毒相互作用的理解。近年来，NoV已被确定为旅行者腹泻的重要肠道病原体。主要研究者有一个独特的机会，研究宿主的遗传决定因素和免疫反应，以NoV胃肠炎在一个大的（n = 600）前瞻性队列的美国旅行者到墨西哥，印度，或秘鲁。我们的长期目标是：1）确定易感性的重要遗传决定因素和宿主对NoV感染的免疫机制，以进一步开发针对NoV的疫苗，以及2）确定可能从疫苗接种中获益最多的脆弱人群。为了实现这些目标，我们提出了以下具体目标：1）评估分泌状态是否是NoV感染风险、感染的临床严重程度和粪便病毒脱落水平的重要决定因素; 2）研究预先存在的针对NoV的抗体在保护免受NoV感染中的作用; 3）评估在患有NoV腹泻的受试者中引发的细胞免疫应答。第一个具体目标将通过唾液样本分泌表型和血清样本基因分型来实现。将采用定量实时PCR和血清抗体转换进行NoV检测。第二个目标将通过评价既存抗NoV抗体和评估检测到的抗体的潜在中和能力，以及体外抑制VLP与组织血型抗原碳水化合物结合试验来实现。第三个目标将通过测量来自粪便标本和来自外周血单核细胞的NoV病毒样颗粒刺激的细胞因子来实现。将研究肠道免疫应答和对NoV感染的全身免疫应答之间的相关性。该项目还将提供必要的培训和技能，使PI成为成功的肠道疾病独立临床研究者。相关性（参见说明）：NoV是食源性疾病的重要肠道病原体，在美国每年感染约2300万人。易感人群包括餐馆顾客、儿童、老年人、住院患者、军人和旅行者。由于感染剂量低、易于传播、环境稳定性和对清洁剂的抗性，NoV被认为是生物恐怖主义的B类候选因子。

DESCRIPTION (provided by applicant): Noroviruses (NoVs) are the most common cause of foodborne illnesses and acute non-bacterial gastroenteritis worldwide. The lack of a cell culture and animal model has hindered progress in understanding host susceptibility and host-viral interactions. Recently, NoVs have been identified as an important enteric pathogen of travelers' diarrhea. The principal investigator has a unique opportunity to study host genetic determinants and immune responses to NoV gastroenteritis in a large (n = 600) prospective cohort of US travelers to Mexico, India, or Peru. Our longterm goals are to: 1) to define important genetic determinants of susceptibility and mechanisms of host immunity to NoV infection to further vaccine development against NoVs, and 2) to identify vulnerable populations who may most benefit from vaccination. In order to achieve these goals, we propose the following specific aims: 1) to evaluate whether secretor status is an important determinant of risk of NoV infection, clinical severity of infection, and level of fecal viral shedding; 2) to study the role of preexisting antibodies to NoVs in protection against NoV infection; 3) to evaluate the cellular immune response elicited in subjects with NoV diarrhea. The 1st specific aim will be accomplished by secretor phenotyping with saliva specimens and genotyping from serum samples. NoV detection will be performed with quantitative real-time PCR and serum antibody conversion. The 2nd aim will be achieved by evaluating for preexisting anti-NoV antibodies and assessing for potential neutralization capacity of detected antibodies, with in vitro inhibition of VLP binding to histo-blood group antigen carbohydrates assays. The 3rd aim will be accomplished by measuring cytokines from fecal specimens and from NoV virus-like particle stimulation of peripheral blood mononuclear cells. The correlation between the intestinal immune response and the systemic immune response to NoV infection will be studied. This project will also provide essential training and skills for the development of the PI into a successful independent clinical investigator of enteric diseases. RELEVANCE (See instructions): NoVs are important enteric pathogens of foodborne diseases and infects approximately 23 million people annually in the US. Susceptible populations include restaurant patrons, children, elderly, institutionalized patients, the military, and travelers. With a low infectious dose, ease of transmission, environmental stability, and resistance to cleansing agents, NoVs are considered as a Category B candidate agent of bioterrorism.