COVID-19 Related Tissue Immunopathology

项目摘要 新型冠状病毒感染（COVID-19）持续爆发，已造成数十万人死亡 破坏了世界各地的社会基础设施。宿主免疫系统过度活跃的免疫病理学 导致了COVID-19的临床严重程度。这项研究将检验病理性T细胞 细胞和B细胞相互作用促进自身抗体产生，以介导重症COVID-19的组织损伤 患者在目标1中，我们将量化对自身抗原的抗体应答的广度和特异性， 新冠肺炎患者。该目的的目标是测量自身抗体的患病率及其功能。 与临床疾病严重程度的关系。在目标2中，我们将定义结构-功能改变 免疫细胞亚群之间的相互作用我们将应用高维度成像质量 对死于SARS-CoV-2感染的个体的尸检样本进行细胞计数。免疫分析会 重点关注B细胞和T细胞的相互作用，以及巨噬细胞、中性粒细胞和间质细胞的其他标志物 区室，以全面绘制LN，脾， 肺心脏和胃肠道针对病毒蛋白和RNA中间体的抗体将使 同时可视化感染的细胞，这将提供进一步的见解之间的关系，病毒 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COVID-19的免疫病理学， 前所未有的细节， COVID相关组织损伤的基础结构。深入了解SARS-CoV-2如何导致宿主病理 可以帮助确定COVID-19治疗的新目标，以造福退伍军人和普通民众 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.