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.

本课题组已确定黄病毒非结构蛋白-1(NS1)是一种关键的免疫逃避蛋白， 对抗补体系统。我们已经确定了一种新的50 kDa分泌机制 NS1与H因子相互作用，抑制C4活化，促进C4b降解。在小鼠中，C4水平 在西尼罗河病毒感染后不久下降，与NS1抗原血症的峰值相关。作为C4-/-和C4+/- 显示出对致命性西尼罗河病毒感染的易感性增加，我们假设人类体内低水平的C4可能 是严重黄病毒病的危险因素。在人类中，补体激活(低C4)立即 是登革热失血性休克的先兆，与登革热综合征的发展相关。 此外，NS1蛋白选择性地与人类细胞结合的机制是基于它们的GAG图谱。 这一高度协作和互动的赠款提案的目标是确定结构和分子 根据黄病毒NS1相对于补体系统的抑制作用，并评价 具有C4等位基因特定拷贝数变异的人更容易感染严重的黄病毒 感染。因此，长期目标是确定ns1在黄病毒免疫发病机制中的作用。 感染。我们将鉴定黄病毒NS1蛋白的补体抑制功能，鉴定 NS1功能的结构基础，并确定C4拷贝基因变异是否与重度 人类感染黄病毒。这笔赠款汇集了三位经验丰富的免疫学家，他们具有特殊的 精通补体、结构生物学和黄病毒致病机制。它还具有国际特色 与加拿大、泰国和尼加拉瓜的黄病毒组织合作。最后，它将提供这两种新颖的 对黄病毒的基本免疫生物学逃避策略的洞察以及与这些进展相关的 临床疾病状态。加强对NS1生物学和结构的理解可能会促进 开发新的抗体或小分子抑制剂来阻断免疫拮抗，增加我们的 了解风险，并确定疫苗或其他类型预防措施的目标人群。