The pulmonary vasculature in lethal COVID-19 and idiopathic pulmonary fibrosis at single-cell resolution

AIMS: Severe acute respiratory syndrome coronavirus-2 infection causes COVID-19, which in severe cases evokes life-threatening acute respiratory distress syndrome (ARDS). Transcriptome signatures and the functional relevance of non-vascular cell types (e.g. immune and epithelial cells) in COVID-19 are becoming increasingly evident. However, despite its known contribution to vascular inflammation, recruitment/invasion of immune cells, vascular leakage, and perturbed haemostasis in the lungs of severe COVID-19 patients, an in-depth interrogation of the endothelial cell (EC) compartment in lethal COVID-19 is lacking. Moreover, progressive fibrotic lung disease represents one of the complications of COVID-19 pneumonia and ARDS. Analogous features between idiopathic pulmonary fibrosis (IPF) and COVID-19 suggest partial similarities in their pathophysiology, yet, a head-to-head comparison of pulmonary cell transcriptomes between both conditions has not been implemented to date. METHODS AND RESULTS: We performed single-nucleus RNA-sequencing on frozen lungs from 7 deceased COVID-19 patients, 6 IPF explant lungs, and 12 controls. The vascular fraction, comprising 38 794 nuclei, could be subclustered into 14 distinct EC subtypes. Non-vascular cell types, comprising 137 746 nuclei, were subclustered and used for EC-interactome analyses. Pulmonary ECs of deceased COVID-19 patients showed an enrichment of genes involved in cellular stress, as well as signatures suggestive of dampened immunomodulation and impaired vessel wall integrity. In addition, increased abundance of a population of systemic capillary and venous ECs was identified in COVID-19 and IPF. COVID-19 systemic ECs closely resembled their IPF counterparts, and a set of 30 genes was found congruently enriched in systemic ECs across studies. Receptor-ligand interaction analysis of ECs with non-vascular cell types in the pulmonary micro-environment revealed numerous previously unknown interactions specifically enriched/depleted in COVID-19 and/or IPF. CONCLUSIONS: This study uncovered novel insights into the abundance, expression patterns, and interactomes of EC subtypes in COVID-19 and IPF, relevant for future investigations into the progression and treatment of both lethal conditions.

• de Rooij, Lpmh
• Becker, L. M.
• Teuwen, L. A.
• Boeckx, B.
• Jansen, S.
• Feys, S.
• Verleden, S.
• Liesenborghs, L.
• Stalder, A. K.
• Libbrecht, S.
• Van Buyten, T.
• Philips, G.
• Subramanian, A.
• Dumas, S. J.
• Meta, E.
• Borri, M.
• Sokol, L.
• Dendooven, A.
• Truong, A. K.
• Gunst, J.
• Van Mol, P.
• Haslbauer, J. D.
• Rohlenova, K.
• Menter, T.
• Boudewijns, R.
• Geldhof, V.
• Vinckier, S.
• Amersfoort, J.
• Wuyts, W.
• Van Raemdonck, D.
• Jacobs, W.
• Ceulemans, L. J.
• Weynand, B.
• Thienpont, B.
• Lammens, M.
• Kuehnel, M.
• Eelen, G.
• Dewerchin, M.
• Schoonjans, L.
• Jonigk, D.
• van Dorpe, J.
• Tzankov, A.
• Wauters, E.
• Mazzone, M.
• Neyts, J.
• Wauters, J.
• Lambrechts, D.
• Carmeliet, P.