COVID-19 Related Tissue Immunopathology

项目摘要 一种新型冠状病毒感染(新冠肺炎)的持续爆发已导致数十万人死亡 并扰乱了世界各地的社会基础设施。高活性宿主免疫系统的免疫病理学 与新冠肺炎的临床严重性有关。这项拟议的研究将检验病理性T细胞 细胞和B细胞相互作用促进自身抗体的产生以介导危重疾病新冠肺炎的组织损伤 病人。在目标1中，我们将量化自身抗原抗体反应的广度和特异性。 新冠肺炎患者。这一目标的目的是测量自身抗体的流行率及其功能 与临床疾病严重程度的关系的意义。在目标2中，我们将定义结构-功能更改 跨多个组织隔间的免疫亚群。我们将应用高维成像质量 SARS-CoV-2感染者尸检标本的细胞学分析免疫分析将会 重点关注B细胞和T细胞的相互作用，以及巨噬细胞、中性粒细胞和间质的其他标记 分区，以全面绘制LN、脾、 肺、心脏和胃肠道。针对病毒蛋白质和RNA中间体的抗体将使 感染细胞的同时可视化，这将提供对病毒之间关系的进一步见解 感染和组织水平的免疫反应。这项拟议的研究将阐明自身抗体如何 可能有助于新冠肺炎的免疫病理机制，并提供细胞 史无前例的细节 COVID相关组织损伤的基础架构。对SARS-CoV-2引起宿主病理的洞察 可以帮助确定新冠肺炎治疗的新目标，使退伍军人和普通民众受益 逍遥法外。

Project Summary An ongoing outbreak of a novel coronavirus infection (COVID-19) has claimed hundreds of thousands of lives and disrupted social infrastructures around the world. Immunopathology from hyperactive host immune system contributes to the clinical severity of COVID-19. The proposed study will test the hypothesis that pathologic T cell and B cell interactions promote autoantibody production to mediate tissue damage in critically ill COVID-19 patients. In Aim 1, we will quantify the breadth and the specificity of antibody responses to self-antigens in COVID-19 patients. The goal of this aim is to measure the prevalence of autoantibodies and their functional significance in relationship to clinical disease severity. In Aim 2, we will define the structural-functional alterations to the immune subsets across multiple tissue compartments. We will apply high-dimensional imaging mass cytometry on autopsy samples from individuals who died from SARS-CoV-2 infection. The immune analyses will focus on B cell and T cell interactions, with additional markers for macrophages, neutrophils, and stromal compartments to comprehensively map the spatial organization of the immune microenvironments in LN, spleen, lung, heart, and the gastrointestinal tract. Antibodies targeting viral proteins and RNA intermediates will enable simultaneous visualization of infected cells, which will provide further insights into the relationship between viral infection and the immune response at the tissue-level. The proposed study will elucidate how autoantibodies may contribute to the immunopathology of COVID-19 and provide cellular unprecedented details on the architecture underlying COVID-related tissue damage. Insights into how SARS-CoV-2 causes host pathology could aid the identification of new targets for COVID-19 treatments to benefit veterans and the general population at large.