Flavivirus NS-1, complement and disease susceptibility

黄病毒 NS-1、补体和疾病易感性

• 批准号: 7672127
• 负责人: John Atkinson
• 金额: $ 29.12万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-09 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7672127
• 关键词: Alleles; Antibodies; Antiviral Agents; Applications Grants; Biology; Canada; Cells; Clinical; Collaborations; Complement; Complement 4b; Complement Activation; Complement Factor H; Complement component C1; Copy Number Polymorphism; Dengue; Development; Disease; Disease susceptibility; Flavivirus; Flavivirus Infections; Fostering; GAG Gene; Gene Dosage; Genes; Goals; Grant; Hemorrhagic Shock; Human; Human Factor H; Immune; Immunity; Immunobiology; Immunologist; Infection; International; Molecular; Mus; Nicaragua; Pathogenesis; Pathologic; Predisposition; Prophylactic treatment; Protein Binding; Proteins; Relative (related person); Risk; Risk Factors; Role; Seasons; Site; Structural Protein; Structure; Syndrome; System; Target Populations; Thailand; Vaccines; Variant; West Nile virus; base; biodefense; depressed; inhibitor/antagonist; insight; novel; research study; small molecule; structural biology

Our group has identified flavivirus non-structural protein-1 (NS1) as a key immune evasion protein that antagonizes the complement system. We have identified a novel mechanism by which the 50 kDa secreted NS1 interacts with factor H, inhibits C4 activation and enhances C4b degradation. In mice, levels of C4 decrease soon after WNV infection, correlating with a spike in NS1 antigenemia. As both C4-/- and C4+/- show increased susceptibility to lethal WNV infection, we hypothesize that low levels of C4 in humans may be a risk factor for severe flavivirus disease. In humans, complement activation (low C4) immediately precedes the onset of dengue hemorrhagic shock and correlates with the development of this syndrome. Further, the mechanism whereby NS1 protein binds selectively to human cells is based on their GAG profile. The goal of this highly collaborative and interactive grant proposal is to identify the structural and molecular basis of the inhibitory actions of flavivirus NS1 relative to the complement system, and to evaluate whether humans with specific gene copy number variation of C4 alleles are more susceptible to severe flavivirus infection. The long term aim, therefore, is to define the role of NS1 in the immunopathogenesis of flavivirus infections. We will characterize the complement inhibitory function of flavivirus NS1 proteins, identify the structural basis of NS1 function and determine whether C4 copy gene variation is associated with severe flavivirus infection in humans. This grant brings together three seasoned immunologists with special expertise in complement, structural biology and flavivirus pathogenesis. It also features international collaborations with flavivirus groups in Canada, Thailand and Nicaragua. Lastly, it will provide both novel insights into the basic immunobiology evasion strategy of flaviviruses as well as relate these advances to clinical disease states. An enhanced understanding of NS1 biology and structure may foster the development of novel antibodies or small molecule inhibitors that block immune antagonism, increase our understanding of risk, and identify target populations for vaccines or other types of prophylaxis.

我们的小组已将非结构性蛋白1（NS1）确定为关键免疫逃避蛋白 对抗补体系统。我们已经确定了一种新的机制，该机制是50 kDa分泌的 NS1与因子H相互作用，抑制C4激活并增强C4B降解。在小鼠中，C4水平 WNV感染后不久降低，与NS1抗原血症中的尖峰相关。作为C4 - / - 和C4 +/- 显示出对致命WNV感染的敏感性增加，我们假设人类的C4水平较低可能 成为严重的黄病毒疾病的危险因素。在人类中，立即补充激活（低C4） 在登革热出血性休克的发作之前，与该综合征的发展相关。 此外，NS1蛋白与人类细胞有选择结合的机制是基于其插入率的。 这个高度协作和互动授予的提案的目的是确定结构和分子 黄病毒NS1相对于补体系统的抑制作用的基础，并评估是否是否 具有C4等位基因的特定基因拷贝数变化的人类更容易受到严重的黄病毒的影响 感染。因此，长期目的是定义NS1在黄病毒的免疫发作中的作用 感染。我们将表征黄素NS1蛋白的补体抑制功能，确定 NS1功能的结构基础，并确定C4复制基因变异是否与严重相关 人类的黄病毒感染。该赠款将三位经验丰富的免疫学家与特殊 补体，结构生物学和黄病毒发病机理方面的专业知识。它还具有国际 与加拿大，泰国和尼加拉瓜的Flavivirus集团的合作。最后，它将提供两个小说 洞悉黄病毒基本免疫生物学逃避策略，并将这些进步与 临床疾病状态。对NS1生物学和结构的增强理解可能会促进 开发阻断免疫拮抗作用的新型抗体或小分子抑制剂，增加我们的 了解风险，并确定疫苗或其他类型预防的目标种群。