Identifying Immune Targets to treat severe COVID-19 lung disease (IT-COVID-19)

While most patients recover from SARS-CoV-2 infection, some progress to acute respiratory distress syndrome requiring mechanical ventilation with a high mortality of 20-30%. This progression might be due to an overwhelming immune reaction. Thus, reducing the hyperinflammation seems to be an ideal therapeutic approach. However, considering the functional heterogeneity of the immune cells, it remains unclear which of the major immune players is the optimal target for a COVID-19 therapy. This is essential, since targeting the wrong immune players might even worsen the disease. Our main hypothesis is that the major detrimental immunological player is a specific population of pathological T cells and that selectively blocking these cells or their bioproducts, (e.g. cytokines, chemokines) will provide a cure for severe COVID-19 patients. We will use our established workflows to perform single-cell RNA-/ TCR-sequencing of lung-infiltrating leukocytes with a focus on T cells and parenchymal lung cells in severe COVID-19. The data analysis will reveal the functional heterogeneity of SARS-CoV-2-specific T cells and establish the pathological interactions between the immune cells and parenchymal lung infected versus non infected cells. Finally, we will test the function of the potential disease-driving cells and/or bioproducts using a recently established airway organoid system. The immediate impact of this project will be a COVID-19 immune atlas which will be key to choose the best target for the already available immune therapies to treat COVID-19 patients in the coming months.