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.

项目概要埃博拉病毒病 (EVD) 幸存者报告了康复后出现的一系列症状这些长期的后遗症严重到足以干扰他们的日常生活，现在已经集中起来。被称为埃博拉后综合症（PES），尽管病毒后症状已造成严重问题。 1995年和2013-2016年埃博拉疫情爆发时，人们对PES发病机制的潜在机制知之甚少。埃博拉病毒 (EBOV) RNA 已在免疫特权部位（例如眼睛和精液）中发现，因此表明病毒可能会持续存在于组织中，随着时间的推移引起持续的抗原刺激，但事实并非如此。所有 PES 病例均可归因于病毒持续存在。自身免疫样，最常见的是针对普通人类的关节痛和肌痛。在幸存者血清中也发现了蛋白质，暗示病毒诱导的自身免疫。病毒特异性抗体反应和自身免疫抗体反应在 PES 的发展中都发挥着作用。我们与杜兰大学的 John Schieeffelin 博士合作，建议分析现有的埃博拉病毒病队列来自塞拉利昂的幸存者及其家庭联系人，已获得发展的临床特征我们的初步研究结果表明，存在针对免疫显性抗原埃博拉病毒的抗体。无症状埃博拉病毒病幸存者的糖蛋白（EBOV GP）与经历过埃博拉病毒病的幸存者有质的不同具体来说，来自无症状个体的抗体会诱导更高的 PES 肌肉骨骼表现。抗体依赖性补体沉积和单核细胞介导的吞噬作用的水平，但不包括中性粒细胞介导的吞噬作用，并且与 PES 个体相比，NK 细胞激活情况有所不同。我们的数据还显示，针对 dsDNA、HSP-60、瓜氨酸组蛋白和 IFNα 的 IgG1 水平升高与 GP 血清阴性 HHC 相比，EVD 幸存者和 GP 血清阳性家庭接触者 (HHC) 因此，该提案的目的是进一步研究自身抗体与埃博拉病毒感染之间的相关性。研究病毒特异性和自身免疫抗体介导的先天免疫细胞激活在 PES，以及这种作用是保护性的还是病理性的。为此，我们建议分析诱导抗体。 Aim 1 和 Aim 2 中针对 EBOV 特异性蛋白的先天效应功能的研究将侧重于识别 PES 患者潜在的自身免疫抗体反应升高，这些目标将共同实现。解决具有不同特异性的不同性质的抗体在影响易感性方面的作用预防 PES 的发展，并可能有助于确定潜在的治疗靶点，以提供适当的治疗为患有 PES 的埃博拉病毒病幸存者提供有效的治疗除了提供免疫学方面的专业知识外，病毒学和埃博拉病毒病，我的发起人和共同发起人，Bronwyn Gunn 博士、John Schiefelin 博士和安东尼·尼古拉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成功地完成这项提案并成为一名研究科学家。