Phenotypic and functional analysis of immune cells during severe COVID-19

重症 COVID-19 期间免疫细胞的表型和功能分析

• 批准号: 457352540
• 负责人: Professorin Dr. Anja Erika Hauser
• 金额: --
• 依托单位: Deutsches Rheuma-Forschungszentrum Berlin (DRFZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/457352540?language=en
• 关键词: Phenotypic; functional; analysis; immune; cells

The consequences of the novel coronavirus disease 2019 (COVID-19) are posing great challenges to the people, public health and healthcare systems worldwide. In order to get the SARS-CoV2 pandemic under control, it is of utmost importance to understand the host response against this virus. On the one hand, characterizing the mechanisms of immune activation will help to identify therapeutic targets in the course of the disease, especially since immune pathology is contributing to tissue damage during COVID-19. On the other hand, an in-depth characterization of the immunological memory response against SARS-CoV2 will help to design efficient, protective vaccination strategies. Here, we propose to combine multiplexed histology with spatially resolved transcriptomic analyses in autopsy tissues, in order to phenotypically characterize and map the immune response during severe COVID-19. We will analyze various time points in the lung as a target organ of the disease, as well as in the corresponding secondary lymphoid organs of the same patients namely the draining lymph nodes and tonsils. We will employ functional fluorescence lifetime imaging in 3D-culture models in order to test the hypothesis that innate mechanisms such as NETosis are one driving force for tissue damage, and assess the communication between macrophages and neutrophils. Since a dysregulated innate immune response against SARS-CoV2 is hypothesized to also impact on the adaptive immune response, we are planning to characterize T cell and B cell responses in the tissues, with a focus on the generation of tissue-specific immunological memory, and on the characterization of the cellular and molecular microenvironment that fosters this process.In a synergistic way, this proposal combines the expertise of the three applicants with respect to pathology, immunology and state-of-the-art imaging technology, in order to elucidate the mechanisms of immune pathology underlying severe COVID-19, and to explore the potential of tissue-specific protection by resident memory cells.

2019新型冠状病毒病（COVID-19）的后果对全球人民、公共卫生和医疗体系构成巨大挑战。为了控制SARS-CoV 2大流行，了解宿主对这种病毒的反应至关重要。一方面，表征免疫激活机制将有助于确定疾病过程中的治疗靶点，特别是因为免疫病理学在COVID-19期间导致组织损伤。另一方面，对SARS-CoV 2免疫记忆反应的深入表征将有助于设计有效的保护性疫苗接种策略。在这里，我们建议将联合收割机多重组织学与尸检组织中的空间分辨转录组学分析相结合，以表型表征和绘制严重COVID-19期间的免疫反应。我们将分析作为疾病靶器官的肺中的不同时间点，以及相同患者的相应次级淋巴器官（即引流淋巴结和扁桃体）中的不同时间点。我们将在3D培养模型中采用功能性荧光寿命成像，以检验先天机制（如NETosis）是组织损伤的驱动力之一的假设，并评估巨噬细胞和中性粒细胞之间的通信。由于针对SARS-CoV 2的先天性免疫应答失调被假设也影响适应性免疫应答，我们计划表征组织中的T细胞和B细胞应答，重点关注组织特异性免疫记忆的产生，以及促进这一过程的细胞和分子微环境的表征。该提案结合了三位申请人在病理学、免疫学和最新成像技术方面的专业知识，以阐明严重COVID-19的免疫病理学机制，并探索驻留记忆细胞的组织特异性保护潜力。