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

该项目旨在测试在新冠肺炎期间，脾是否是病毒和炎症介质的重要来源。细胞因子风暴的诱导是SARS和新冠肺炎病原性炎症的原因。由SARS-CoV-2感染的脾CD169+巨噬细胞被认为通过促炎症细胞死亡促进病毒传播和过度炎症(Park Nat Rev免疫2020；冯BioRxif 2020)。我们的跨学科团队拥有独特的专业知识，能够在系统性感染期间将脾CD169+巨噬细胞作为关键参与者(ErcoliNatMicrobiol2018年；Chung Altex 2019)，并使用已获准在新冠肺炎上工作的人脾体外灌流模型(REC18/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整个器官体外人脾灌流模型来描述全身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。我们将测试这些CD169+组织巨噬细胞作为病毒系统性传播中心的假设。主要成果将是确定脾内SARS-CoV-2感染组织巨噬细胞期间的关键事件。这些结果将为疾病过程和优化系统宿主定向治疗策略提供重要的见解。

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.