Characterisation at the organ level of SARS-CoV-2-induced macrophage-dependent inflammation in the spleen

该项目旨在测试脾脏是否是COVID-19期间病毒和炎症介质的重要来源。细胞因子风暴的诱导是SARS和COVID-19致病性炎症的原因。SARS-CoV-2感染脾CD169+巨噬细胞可通过促炎细胞死亡促进病毒传播和过度炎症（Park Nat Rev Immunol 2020; Feng BioRxif 2020）。我们的跨学科团队在脾脏CD169+巨噬细胞作为全身性感染的关键角色方面具有独特的专业知识（Ercoli NatMicrobiol 2018; Chung ALTEX 2019），并使用已被授权用于COVID-19研究的人脾脏离体灌注模型（REC 18/EM/0057）。我们现在已经证实，人脾CD169+组织巨噬细胞亚群既表达SARS-CoV-2受体ACE2，也表达尖峰修饰蛋白酶TMPRSS2。我们现在建议利用我们的全器官离体人脾脏灌注模型来表征全身性感染早期阶段的步骤。这种设置允许随着时间的推移对感染过程进行详细分析。我们将验证这些CD169+组织巨噬细胞作为病毒全身传播中心的假设。主要输出将是脾脏组织巨噬细胞感染SARS-CoV-2期间关键事件的定义。这些结果将为了解疾病过程和优化系统宿主定向治疗策略提供重要见解。

This project aims to test if the spleen is a significant source of virus and inflammatory mediators during COVID-19. The induction of a cytokine storm is the cause of pathogenic inflammation both in SARS and COVID-19. Infection of splenic CD169+ macrophages by SARS-CoV-2 has been proposed to contribute to viral spread and excessive inflammation through pro-inflammatory cell death (Park Nat Rev Immunol 2020; Feng BioRxif 2020). Our interdisciplinary team has unique expertise with splenic CD169+ macrophages as key players during systemic infection (Ercoli NatMicrobiol 2018; Chung ALTEX 2019), and with use of a human spleen ex vivo perfusion model that has been authorised for work on COVID-19 (REC 18/EM/0057). We have now confirmed that a subpopulation of human splenic CD169+ tissue macrophages express both the SARS-CoV-2 receptor ACE2 and the spike-modifying protease TMPRSS2. We now propose to exploit our whole organ ex vivo human spleen perfusion model to characterise the steps in the early phases of systemic infection. This set up allows for detailed analysis of the infectious process over time. We will test the hypothesis that these CD169+ tissue macrophages serve as a hub for systemic spread of the virus. The main outputs will be the definition of key events during tissue macrophage infection by SARS-CoV-2 in the spleen. These outputs will provide important insights into the disease process and for optimising systemic host directed treatment strategies.