Structural Determinants of Human Antibodies neutralizing the Ebola Virus

中和埃博拉病毒的人类抗体的结构决定因素

基本信息

批准号：
9304960
负责人：
Jens Meiler
金额：
$ 23.54万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304960
关键词：
Affinity Algorithms Antibodies Antibody Repertoire Antigen-Antibody Complex Binding Biological Central Africa Collaborations Communities Complement Complex Computational Biology Computer Simulation Crystallization Data Databases Development Disease Outbreaks Ebola virus Electron Microscopy Engineering Europe Family Filoviridae Filovirus Frankfurt-Marburg Syndrome Virus Geography Glycoproteins Goals Human Hybrids Immune Immune response Infection Influenza Laboratories Letters Maps Membrane Glycoproteins Methods Modeling Modernization Mutation Positioning Attribute Procedures Property Proteins Protocols documentation Publications Research Research Personnel Resolution Somatic Mutation Structure System Technology Testing Therapeutic antibodies Time Uganda Universities Vaccination Vaccines Viral Viral Hemorrhagic Fevers Virus Western Africa Work data management density design follow-up high risk improved innovation member neutralizing antibody next generation sequencing novel structural biology therapeutic development therapeutic vaccine vaccination strategy ward

项目摘要

SUMMARY The filovirus family includes Marburg and Ebola viruses, most of which cause highly lethal hemorrhagic fever. The first filovirus was identified when it sickened laboratory workers in Europe in 1967. Since then, filo- viruses have re-emerged multiple times, with modern strains conferring greater lethality (~90%). Ebola virus is typically found in Central Africa, but re-emerged in Western Africa in 2014 to cause an on-going outbreak un- precedented in magnitude and geographic spread that has already claimed the lives of thousands of people. There is also a current outbreak of Marburg virus in Uganda. Last month structural data on several neutralizing antibodies (Abs) in complex with the viral target enve- lope surface glycoprotein (GP) became available to us, enabling for the first time the research proposed within this PAPID proposal. Specifically, co-crystal structures of one Ab with the Marburg and Ebola GP, respectively, as well as electron microscopy (EM) density maps for six additional Abs. It is our Goal to investigate the shared structural determinants of human Abs neutralizing the filovirus. While the present study thereby focuses on the biological question of the immune response to an infection by the Ebola and Marburg viruses, it has the potential to facilitate development of therapeutic strategies by others. Within the scope of this R21 proposal we pursue three goals: Aim 1 creates atomic detail models of the Ab/GP interface for all seven Abs with available EM density maps. We will use the co-crystal structure to test our computational protocol, and then apply it to the remaining six cases. As a result, we will obtain a map of critical structural determinants an Ab needs to fulfill for being neutralizing. Aim 2 will identify novel Abs from the repertoire of naïve subjects that are likely to neutralize Ebola and/or Marburg viruses with a limited set of muta- tions. We also will compare the Ab repertoires of filovirus-naïve (i.e. not previously infected) humans to those of immune (previously infected) subjects available to us. These Abs from naïve subjects are important, as they could evolve into neutralizing Abs upon infection or vaccination. We will redesign these Abs computationally to bind and neutralize Ebola and/or Marburg viruses, to increase the pool of known neutralizing Abs, paving the way for a successful vaccination strategy. In Aim 3 we will characterize these Abs experimentally for binding and neutralization activity. While ultimately a structural characterization of the most promising of these Abs is planned, it is outside the scope of the R21 proposal.

概括丝状病毒家族包括马尔堡病毒和埃博拉病毒，其中大多数会导致高度致命的出血性病毒 1967 年，当欧洲实验室工作人员患病时，发现了第一个丝状病毒。病毒已多次重新出现，现代毒株具有更大的致死率（约 90%）。通常在中非发现，但 2014 年在西非重新出现，导致持续爆发其规模和地理范围之广前所未有，已夺去了数千人的生命。乌干达目前也爆发马尔堡病毒。上个月关于几种中和抗体（Abs）与病毒靶标复合物的结构数据我们可以使用 lope 表面糖蛋白（GP），首次实现了该研究中提出的研究具体来说，一种抗体分别与马尔堡和埃博拉 GP 的共晶结构，以及另外六种抗体的电子显微镜 (EM) 密度图我们的目标是研究共享的抗体。人类抗体中和丝状病毒的结构决定因素，而本研究的重点是。关于埃博拉病毒和马尔堡病毒感染的免疫反应的生物学问题，它具有促进他人制定治疗策略的潜力。在 R21 提案的范围内，我们追求三个目标：目标 1 创建原子细节模型所有七种 Ab 的 Ab/GP 接口以及可用的 EM 密度图我们将使用共晶结构进行测试。我们的计算协议，然后将其应用于其余六种情况，结果，我们将获得一张图。目标 2 将确定抗体中和所需的关键结构决定因素。可能用一组有限的突变来中和埃博拉和/或马尔堡病毒的天真的受试者的全部技能我们还将比较未感染丝状病毒（即以前未感染过）的人类的抗体库。我们可以获得免疫（以前感染过）的受试者的这些抗体，因为它们很重要。在感染或接种疫苗后可能会进化为中和抗体，我们将通过计算重新设计这些抗体。结合并中和埃博拉和/或马尔堡病毒，以增加已知中和抗体库，为在目标 3 中，我们将通过实验对这些抗体进行结合和表征。最终，这些抗体中最有希望的结构特征是计划中，它超出了 R21 提案的范围。