Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome

定义抗体在埃博拉后综合症中的保护或病理作用

基本信息

批准号：
10752441
负责人：
Jalene Velazquez
金额：
$ 4.39万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752441
关键词：
2019-nCoV Acute Antibodies Antibody Response Antigen-Antibody Complex Antigens Arthralgia Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Binding Biological Assay Cells Chaperonin 60 Clinical Cognition Collaborations Complement Data Deposition Development Disease Disease Outbreaks Ebola Ebola Hemorrhagic Fever Ebola virus Epidemic Eye Fc Receptor Fc domain Filovirus Glycoproteins Goals Histones Household Human Humoral Immunities IgG1 Immune Immunodominant Antigens Immunology Incubated Individual Infection Inflammatory Influenza Interferon alpha Life Long COVID Measures Mediating Mentors Musculoskeletal Myalgia NK Cell Activation Natural Killer Cells Neurologic Symptoms Pathogenesis Pathogenicity Pathologic Pathology Patients Phagocytosis Polysaccharides Predisposition Prevention Property Proteins Quality of life Recombinants Recovery Reporting Research Resolution Role SARS-CoV-2 infection Scientist Seminal fluid Serum Severities Shapes Sierra Leone Site Specificity Structure Survivors Symptoms Syndrome Time Tissues Training Universities Viral Virus Virus Diseases autoimmune inflammation biophysical properties cell type chemokine cohort cytokine ds-DNA effective therapy experience experimental study extracellular falls immune activation long-term sequelae mRNA Expression monocyte nano-string neutrophil new therapeutic target novel patient mobility programs recruit seropositive skills therapeutic target therapeutic vaccine viral RNA virology

项目摘要

PROJECT SUMMARY Survivors of Ebola virus disease (EVD) have reported a wide range of symptoms following recovery from infection. These long-term sequelae are severe enough to interfere with their daily lives and are now collectively referred to as post-Ebola syndrome (PES). Although post-viral symptoms have posed a serious problem in the Ebola outbreaks of 1995 and 2013-2016, little is known about the underlying mechanism of PES pathogenesis. Ebola virus (EBOV) RNA has been found in immune-privileged sites, such as the eye and semen, so it is suggested that the virus may persist in tissues to cause continued antigenic stimulation over time. However, not all cases of PES can be attributed to viral persistence. Most of the symptoms that survivors experience are autoimmune-like, the most common being arthralgias and myalgias. Autoantibodies against common human proteins have also been found in survivor serum, alluding to virus-induced autoimmunity. We hypothesize that both virus-specific and autoimmune antibody responses play a role in the development of PES. Through a collaboration with Dr. John Schieffelin at Tulane University, we propose to analyze an existing cohort of EVD survivors and their household contacts from Sierra Leone that have been clinically characterized for development of PES. Our preliminary findings revealed that antibodies against the immunodominant antigen, the Ebola glycoprotein (EBOV GP), in asymptomatic EVD survivors were qualitatively different from survivors experiencing musculoskeletal manifestations of PES. Specifically, antibodies from asymptomatic individuals induced higher levels of antibody-dependent complement deposition and monocyte-mediated phagocytosis, but not neutrophil- mediated phagocytosis, and differed in NK cell activation profiles compared with individuals with PES. In addition, our data has also revealed that IgG1 levels against dsDNA, HSP-60, citrullinated histone, and IFNα are elevated in EVD survivors and GP-seropositive household contacts (HHC) compared to GP-seronegative HHC, indicating a correlation between autoantibodies and EBOV infection. Thus, the purpose of this proposal is to further investigate the role of both virus-specific and autoimmune antibody-mediated innate immune cell activation in PES, and whether this role is protective or pathologic. To do so, we propose to analyze antibodies for induction of innate effector function against EBOV-specific proteins in Aim 1 and Aim 2 will focus on the identification of potential autoimmune antibody responses that are elevated in individuals with PES. Together, these aims will address the role of qualitatively different antibodies with varying specificities in shaping susceptibility to/protection from the development of PES and may help to identify potential therapeutic targets to provide proper and effective treatment to EVD survivors suffering from PES. In addition to providing expertise in immunology, virology, and Ebola virus disease, my sponsor and co-sponsors, Drs. Bronwyn Gunn, John Schieffelin, and Anthony Nicola have developed a comprehensive training plan aimed at providing me with the necessary skills needed for me to succeed in this proposal and as a research scientist.

项目摘要埃博拉病毒疾病（EVD）的幸存者报告了从感染。这些长期后遗症很严重，可以干扰他们的日常生活称为埃博拉综合征（PES）。尽管病毒后症状已被定位为严重的问题 1995年和2013 - 2016年的埃博拉病毒爆发对PES发病机理的潜在机制知之甚少。埃博拉病毒（EBOV）RNA已在免疫挑战的部位（例如眼睛和精液）中发现，因此建议该病毒可能会持续在组织中引起持续的抗原刺激。但是，不是所有PE的病例都可以归因于病毒持久性。生存经历的大多数症状是自身免疫性状，最常见的是雅思拉和肌痛。反对普通人的自身抗体还发现了蛋白质在生存血清中，暗示了病毒诱导的自身免疫性。我们假设这一点病毒特异性和自身免疫性抗体反应都在PES的发展中起作用。通过一个与杜兰大学的John Schieffelin博士合作，我们建议分析现有的EVD队列幸存者及其来自塞拉利昂的家庭接触已在临床上进行开发特征 pes。我们的初步发现表明，针对免疫主导抗原的抗体，埃博拉病毒糖蛋白（EBOV GP），在不对称的EVD表面上与表面经验有质量不同 PES的肌肉骨骼表现。具体而言，来自非对称个体的抗体诱导较高抗体依赖性补体沉积和单核细胞介导的吞噬作用的水平，但未与PES相比，NK细胞活化谱的介导的吞噬作用，并且在NK细胞活化谱中不同。此外，我们的数据还表明，针对DsDNA，HSP-60，柠檬硫化组蛋白和IFNα的IgG1水平升高在EVD存活和GP阳性家庭接触（HHC）中，与GP-Seronegative HHC相比自身抗体与EBOV感染之间的相关性。这是该提议的目的是进一步研究病毒特异性和自身免疫性抗体介导的先天免疫细胞激活的作用 PES，以及该作用受到保护还是病理。为此，我们建议分析抗体的诱导 AIM 1和AIM 2中针对EBOV特异性蛋白质的先天效应子功能将集中在识别上 PES个体中升高的潜在自身免疫性抗体反应。这些目标将在一起解决定性不同抗体的作用，并具有不同规格在塑造敏感性中的作用避免/免受PES的开发，并可能有助于确定潜在的治疗靶点以提供适当的和有效的治疗方法，以遭受PES的生存。除了提供免疫学专业知识外，病毒学和埃博拉病毒疾病，我的赞助商和共同发起人，博士。 Bronwyn Gunn，John Schieffelin和安东尼·尼古拉（Anthony Nicola）制定了一项全面的培训计划，旨在为我提供必要的技能我需要在该提案中成功并成为一名研究科学家。