Single-cell-sequencing in SARS-COV-2-infected hamsters sheds light on endothelial cell involvement in COVID-19

Abstract

<b>Background:</b> Pulmonary and systemic immune responses influence disease severity in COVID-19, and could be key to therapeutic strategies. <b>Aims and objectives:</b> To investigate cellular mechanisms contributing to defense or fostering detrimental inflammatory lung injury, focusing on the clinically ill-defined involvement of endothelial cells. <b>Methods:</b> Using SARS-CoV-2-infected Syrian and Roborovski hamsters as models for moderate and severe COVID-19, respectively, a detailed and longitudinal analysis of systemic and pulmonary quantitative and qualitative immune responses was conducted. Hamster omics were corroborated with datasets from COVID-19 patients. <b>Results:</b> By integrating data from COVID-19 patients, inter-species concordance of cellular and molecular host-pathogen interactions was demonstrated. In moderate disease the earliest and strongest transcriptional response following SARS-CoV-2 infection, including pro-inflammatory genes, was exerted by monocyte-derived macrophages in lungs, while epithelial cells showed only weak gene expression program changes. Notably, endothelial cells showed no evidence for infection but reacted by strong and early expression of anti-viral as well as pro-inflammatory and T cell recruiting genes, with variations depending on cell subtypes. <b>Conclusions:</b> Analysis of Syrian hamsters infected with SARS-CoV-2 identified cell type-specific effector functions, providing detailed insights into mechanisms of COVID-19, thus informing therapeutic strategies. Extended investigations in highly susceptible Roborosvki dwarf hamsters will complement our picture of moderate and severe disease courses.