Pathogenesis and Antivirals for Noroviruses

诺如病毒的发病机制和抗病毒药物

• 批准号: 9292240
• 负责人: Robert L. Atmar
• 金额: $ 36.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9292240
• 关键词: Acute; Adult; Affinity; Age; Antibodies; Antibody Diversity; Antibody Repertoire; Antibody Response; Antigenic Variation; Antigens; Antiviral Agents; Antiviral Therapy; Binding; Biological; Biological Assay; Blocking Antibodies; Capsid Proteins; Centers for Disease Control and Prevention (U.S.); Child; Chronic; Cloning; Collaborations; Development; Disease Outbreaks; Dissection; Drug Design; Drug Kinetics; Elderly; Epidemic; Evaluation; Exposure to; Frequencies; Funding; Gastroenteritis; Generations; Genetic; Genetic Transcription; Genetic Variation; Genotype; Goals; High-Throughput Nucleotide Sequencing; Human; Humoral Immunities; Illness Days; Immune response; Immunocompetent; Immunocompromised Host; Immunoglobulins; In Vitro; Individual; Infection; Light; Location; Long-Term Care; Measures; Medicine; Metabolic; Methods; Molecular; Monoclonal Antibodies; Mutation; Norovirus; Pathogenesis; Peptide Hydrolases; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasmablast; Polysaccharides; Population; Populations at Risk; Prevention; Prevention strategy; Property; Prophylactic treatment; RNA replication; Reagent; Reporting; Research; Risk; Sampling; Serum; Source; Specificity; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Therapeutic Uses; Time; Toxicology; United States; Variant; Viral; Viral reservoir; Virus; Virus Shedding; age group; antigen binding; base; design; drug candidate; economic impact; health economics; high throughput screening; human monoclonal antibodies; immunological status; improved; inhibitor/antagonist; mimetics; molecular diagnostics; particle; preclinical trial; prevent; prophylactic; response; small molecule inhibitor; treatment strategy; vaccine development; viral RNA; virus genetics; young adult

PROJECT SUMMARY: Project 1 The focus of Project 1 is to increase our understanding of the pathogenesis of norovirus infection and to develop treatment and prevention strategies that can be applied to infected and at risk populations. Human noroviruses are the most common cause of epidemic and sporadic gastroenteritis in the United States, causing both significant health and economic impact, but we currently have only non-specific measures to prevent and treat infection. Our prior research has shown that persons with serum antibody that blocks binding of viral particles to putative glycan attachment factors have decreased risks of illness and infection after exposure to virus, and that following infection such blocking antibodies can develop against heterologous strains. Nevertheless, a major potential barrier to vaccine development is the significant genetic and antigenic variation that occurs. Chronic infection among immunocompromised patients has been proposed as one source of emergent variants. We hypothesize that infections in children and elderly individuals are another source of viral variants. In Specific Aim 1 we will determine whether the frequency of emergent variants is greater in children or the elderly compared to immunocompetent adults, and the frequency of these variants will be contrasted with that observed in an immunocompromised population. The potential impact of genetic changes on VP1 structures (e.g., in histoblood group antigen binding specificities) will be assessed in collaboration with Project 3. Viral strains collected in this project will also be used in cultivation studies in Project 2. In Specific Aim 2, we will perform studies to better understand the humoral immune response induced following infection. We will test the hypothesis that the generation of antibody responses to genotypes distinct from the infecting strain is more common in immunocompetent adults than in children. Human monoclonal antibodies will be made by cloning the heavy and light chain variable domains from plasmablasts generated during acute infection, and expressing these in combination with immunoglobulin constant domains. Antibody reactivity and the ability of the antibodies to block virus-glycan interactions against homotypic and heterotypic strains will be determined. Antibodies that block virus-glycan interactions for a large number of genotypes may have value for use in prophylaxis of risk groups. In Specific Aim 3, we will use an integrated strategy including structure-based inhibitor design, synthetic medicinal chemistry, structure activity relationship analysis, and toxicological studies to develop and characterize antivirals targeting the viral protease. Structural information about key inhibitors developed in this aim will be obtained in collaboration with Project 3. Monoclonal antibodies and antiviral agents developed in Aims 2 and 3 will be evaluated for activity in RNA expression and replication systems developed in Project 2. Overall, these studies are designed to understand and evaluate the importance of age and immune status on virus variation and on the development of potential humoral immunity and to develop reagents that can be used to prevent or treat norovirus infection.

项目概要：项目1 项目1的重点是增加我们对诺如病毒感染发病机制的了解，并 制定可适用于受感染和高危人群的治疗和预防战略。人类 诺如病毒是美国流行性和散发性胃肠炎的最常见原因， 造成重大的健康和经济影响，但我们目前只有非具体措施， 预防和治疗感染。我们先前的研究表明，具有血清抗体的人， 病毒颗粒与假定的聚糖附着因子的结合降低了疾病和感染的风险 在暴露于病毒后，以及在感染后，这种阻断抗体可以产生抗异源性抗体， 菌株然而，疫苗开发的一个主要潜在障碍是重要的遗传和抗原性缺陷。 发生的变化。免疫功能低下患者中的慢性感染被认为是一种 紧急变体的来源。我们假设儿童和老年人的感染是另一种 病毒变体的来源。在具体目标1中，我们将确定紧急变体的频率是否 儿童或老年人的变异率高于免疫正常的成人， 将与免疫功能低下人群中观察到的结果进行对比。基因的潜在影响 VP 1结构上的变化（例如，在组织血液组中，抗原结合特异性）将在 与项目3合作。本项目收集的病毒株也将用于 项目2.在具体目标2中，我们将进行研究，以更好地了解体液免疫反应 感染后诱发。我们将检验这样一个假设，即抗体的产生对 与感染菌株不同的基因型在免疫活性成人中比在儿童中更常见。 人单克隆抗体将通过克隆来自人的重链和轻链可变结构域来制备。 急性感染期间产生的浆母细胞，并与免疫球蛋白结合表达这些浆母细胞 恒定域抗体反应性和抗体阻断病毒-聚糖相互作用的能力 将确定针对同型和异型菌株的抗性。阻断病毒-聚糖相互作用的抗体 因为大量的基因型可能具有用于预防危险群体的价值。在具体目标3中，我们 将采用综合策略，包括基于结构的抑制剂设计，合成药物化学， 结构活性关系分析和毒理学研究，以开发和表征抗病毒药物 靶向病毒蛋白酶。将获得在此目标下开发的关键抑制剂的结构信息 与项目3合作。在目标2和3中开发的单克隆抗体和抗病毒剂将 评价了在项目2中开发的RNA表达和复制系统中的活性。总的来说，这些 研究旨在了解和评估年龄和免疫状态对病毒变异的重要性 和潜在的体液免疫的发展，并开发可用于预防或 治疗诺如病毒感染。