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

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.