Longitudinal omics in Syrian hamsters integrated with human data unravel complexity of moderate immune responses to SARS-CoV-2

Nouailles, Geraldine; Wyler, Emanuel; Pennitz, Peter; Postmus, Dylan; Vladimirova, Daria; Kazmierski, Julia; Pott, Fabian; Dietert, Kristina; Mülleder, Michael; Farztdinov, Vadim; Obermayer, Benedikt; Wienhold, Sandra-Maria; Andreotti, Sandro; Höfler, Thomas; Sawitzki, Birgit; Drosten, Christian; Sander, Leif Erik; Suttorp, Norbert; Ralser, Markus; Beule, Dieter; Gruber, Achim Dieter; Goffinet, Christine; Landthaler, Markus; Trimpert, Jakob; Witzenrath, Martin

In COVID-19, the immune response largely determines disease severity and is key to therapeutic strategies. Cellular mechanisms contributing to inflammatory lung injury and tissue repair in SARS-CoV-2 infection, particularly endothelial cell involvement, remain ill-defined. We performed detailed spatiotemporal analyses of cellular and molecular processes in SARS-CoV-2 infected Syrian hamsters. Comparison of hamster single-cell sequencing and proteomics with data sets from COVID-19 patients demonstrated inter-species concordance of cellular and molecular host-pathogen interactions. In depth vascular and pulmonary compartment analyses (i) supported the hypothesis that monocyte-derived macrophages dominate inflammation, (ii) revealed endothelial inflammation status and T-cell attraction, and (iii) showed that CD4+ and CD8+ cytotoxic T-cell responses precede viral elimination. Using the Syrian hamster model of self-limited moderate COVID-19, we defined the specific roles of endothelial and epithelial cells, among other myeloid and non-myeloid lung cell subtypes, for determining the disease course.