Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS)

约翰·霍普金斯大学 SARS-CoV-2 发病机制和免疫卓越中心 (JH-EPICS)

• 批准号: 10221904
• 负责人: ANDREA L COX
• 金额: $ 406.72万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221904
• 关键词: 2019-nCoV; Address; Affect; Age; Antibodies; Antibody Response; Antigens; Basic Science; Biological Assay; Biometry; COVID-19; Cell surface; Cells; Cessation of life; Clinical; Clinical Sciences; Collaborations; Communicable Diseases; Complement; Complex; Coupled; Data Analyses; Development; Diabetes Mellitus; Disease; Ensure; Enzyme-Linked Immunosorbent Assay; Epidemiologic Monitoring; Epidemiology; Ethnic Origin; Evaluation; Flow Cytometry; Foundations; Gender; Goals; HIV; Health; Healthcare Systems; Heart Diseases; Human; Immune; Immune response; Immunity; Immunoglobulin Class Switching; Immunology; Immunomodulators; Infant; Infection; Inflammasome; Inflammatory Response; Infrastructure; Interdisciplinary Study; International; Leadership; Mediating; Metabolic; Methods; Mission; Modeling; Monoclonal Antibody Therapy; Myeloid-derived suppressor cells; Organ Transplantation; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Peripheral Blood Mononuclear Cell; Population; Prospective cohort; Proteins; Protocols documentation; Public Health; Race; Reagent; Regimen; Reporting; Research; Research Activity; Research Personnel; Research Project Grants; Resources; Respiratory Tract Infections; Risk; Sampling; Science; Serologic tests; Serological; Severities; Severity of illness; Sex Differences; Solid; Stains; Statistical Data Interpretation; Statistical Models; Surrogate Markers; Symptoms; T-Lymphocyte; Testing; Therapeutic; Training; Translational Research; Ursidae Family; Vaccine Design; Viral; Viral Pathogenesis; Virus; age difference; antibody-dependent cell cytotoxicity; base; biosafety level 3 facility; comorbidity; coronavirus disease; design; experimental study; gender difference; innate immune sensing; insight; intersectionality; male; neutralizing antibody; new therapeutic target; novel; novel marker; pandemic disease; racial difference; response; sample fixation; sex; single cell analysis; therapeutic evaluation; therapy development; vaccine candidate; vaccine development; vaccine evaluation; virology

Johns Hopkins has broad expertise in the science of human health, with viral immunity, pathogenesis, epidemiology, biostatistics, and surveillance emerging as integral components of the multidisciplinary research mounted at Johns Hopkins during the current pandemic. We propose development of a Serological Sciences Center of Excellence: the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS). The overarching goal of JH-EPICS is to distinguish immune responses that protect from those that cause pathology during infection. Under the Multiple PI leadership of Drs. Klein and Cox, the JH-EPICS Administrative Core will ensure resources and samples are available to systematically evaluate innate, T cell, and antibody responses to SARS-CoV-2 in peripheral blood mononuclear cells and serological samples from COVID-19 patients sampled longitudinally. JH-EPICS contains three interconnecting Research Projects (RPs). RP1 focuses on innate immune sensing and activation of the human inflammasome by SARS-CoV-2, with evaluation of how anti-SARS-CoV-2 antibodies modulate innate sensing. RP2 uses a novel flow-cytometry based platform that enables single cell analysis of traditional cell surface markers combined with intracellular staining for proteins involved in metabolic programming. Using this platform, we have identified distinct myeloid derived suppressor cells (MDSCs) and T cells abundant in COVID-19. RP1 will characterize these MDSCs, while RP2 will explore novel populations of T cells identified in COVID-19 patients. RP2 will also define novel biomarkers in order to predict severity of disease, track the course of disease, and define novel surrogate markers for testing therapeutic regimens. Together, RP1 and RP2 will identify novel therapeutic targets. In RP3, the magnitude, duration, and class switching of SARS-CoV-2-specific antibody isotypes as well as virus- specific neutralizing antibody responses will be analyzed and compared with non-neutralizing antibody functions, e.g., complement fixation and antibody-dependent cellular cytotoxicity, using a novel core set of serological assays. A centralized Virology Reagent Core will provide antigen for ELISAs, reagents to identify virus-specific immune cell populations, inactivated SARS-CoV-2 viruses, methods for quantifying SARS-CoV- 2, and access to biosafety level 3 facilities and training needed to perform any experiments involving live SARS-CoV-2. The Analysis Resource Core will provide statistical modeling and analysis to frame and test hypotheses about the mechanisms mediating the severity of COVID-19 as well as the intersectionality of sex, gender, age, and racial differences in immune mechanisms of COVID-19. In concert with the trans-network collaborations, this research will provide significant insights into pathologic immune responses to SARS-CoV-2, identification of novel therapeutic targets, and definition of immunity against SARS-CoV-2 infection. By uncovering the correlates of protective immunity, JH-EPICS research will further enhance vaccine design and evaluation of vaccine candidates.

约翰霍普金斯在人类健康科学方面拥有广泛的专业知识，包括病毒免疫，发病机制， 流行病学、生物统计学和监测是多学科研究的组成部分 在当前的大流行期间，在约翰霍普金斯大学建立了。我们建议发展血清学科学 卓越中心：约翰霍普金斯SARS-CoV-2发病机制和免疫卓越中心 （JH-EPICS）。JH-EPICS的总体目标是区分保护免受那些免疫反应的免疫反应。 在感染过程中引起病理变化。在Klein博士和考克斯博士的多重PI领导下，JH-EPICS 行政核心将确保资源和样本可用于系统地评估先天性，T细胞， 和SARS-CoV-2的抗体反应， COVID-19患者纵向采样。JH-EPICS包含三个相互关联的研究项目（RP）。 RP 1主要研究SARS-CoV-2对人类炎性小体的先天免疫感应和激活， 评估抗SARS-CoV-2抗体如何调节先天感应。RP 2使用了一种新的流式细胞术 该平台能够对传统细胞表面标记物进行单细胞分析， 对参与代谢程序的蛋白质进行染色。利用这个平台，我们已经确定了不同的骨髓 衍生的抑制细胞（MDSC）和COVID-19中丰富的T细胞。RP 1将对这些MDSC进行表征， 而RP 2将探索在COVID-19患者中发现的新型T细胞群。RP 2也将定义新的 生物标志物，以预测疾病的严重程度，跟踪疾病的进程，并确定新的替代 用于测试治疗方案的标记物。RP 1和RP 2将共同确定新的治疗靶点。在 RP 3、SARS-CoV-2特异性抗体同种型的强度、持续时间和类别转换以及病毒- 将分析特异性中和抗体应答，并与非中和抗体进行比较 功能，例如，补体结合和抗体依赖性细胞毒性，使用一种新的核心集， 血清学测定。一个集中的病毒学试剂核心将为ELISA提供抗原， 病毒特异性免疫细胞群、灭活的SARS-CoV-2病毒、定量SARS-CoV的方法， 2、获得生物安全3级设施和进行任何涉及活体的实验所需的培训 SARS-CoV-2.分析资源核心将为框架和测试提供统计建模和分析。 关于调节COVID-19严重程度的机制以及性别交叉性的假设， COVID-19免疫机制的性别、年龄和种族差异。与跨网络合作 合作，这项研究将提供对SARS-CoV-2的病理免疫反应的重要见解， 新的治疗靶点的鉴定和针对SARS-CoV-2感染的免疫的定义。通过 揭示保护性免疫的相关性，JH-EPICS研究将进一步加强疫苗设计， 评价候选疫苗。