Rapid endotheliitis and vascular damage characterize SARS‐CoV‐2 infection in a human lung‐on‐chip model

• Published in: EMBO reports Vol. 22; no. 6; pp. e52744 - n/a
• Main Authors: Thacker, Vivek V, Sharma, Kunal, Dhar, Neeraj, Mancini, Gian‐Filippo, Sordet‐Dessimoz, Jessica, McKinney, John D
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 04.06.2021; John Wiley and Sons Inc
• Subjects: alveolar models; Alveoli; Antibodies; COVID‐19; Cytokine storm; Cytokines; Damage prevention; Endothelial cells; Epithelial cells; Epithelium; Immune system; Infections; Inflammation; Inflammatory response; Integrity; Interleukin 6; Interleukin 6 receptors; Lungs; Microenvironments; Microvasculature; Monoculture; organ‐on‐chip; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; vasculitis; Viral diseases; Virions; COVID-19; interleukin 6; alveolar models; vasculitis; organ-on-chip
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202152744

Severe cases of SARS‐CoV‐2 infection are characterized by hypercoagulopathies and systemic endotheliitis of the lung microvasculature. The dynamics of vascular damage, and whether it is a direct consequence of endothelial infection or an indirect consequence of an immune cell‐mediated cytokine storm remain unknown. Using a vascularized lung‐on‐chip model, we find that infection of alveolar epithelial cells leads to limited apical release of virions, consistent with reports of monoculture infection. However, viral RNA and proteins are rapidly detected in underlying endothelial cells, which are themselves refractory to apical infection in monocultures. Although endothelial infection is unproductive, it leads to the formation of cell clusters with low CD31 expression, a progressive loss of barrier integrity and a pro‐coagulatory microenvironment. Viral RNA persists in individual cells generating an inflammatory response, which is transient in epithelial cells but persistent in endothelial cells and typified by IL‐6 secretion even in the absence of immune cells. Inhibition of IL‐6 signalling with tocilizumab reduces but does not prevent loss of barrier integrity. SARS‐CoV‐2‐mediated endothelial cell damage thus occurs independently of cytokine storm. SYNOPSIS In a human lung‐on‐chip model maintained at an air‐liquid interface exposed to SARS‐CoV‐2, endothelial lung microvascular cells are infected via alveolar epithelial cells, leading to persistent endothelial cell inflammation and loss of barrier integrity. Endothelial cells can be infected by SARS‐CoV‐2 via alveolar epithelial cells, but this infection is not productive. Inflammation triggered by SARS‐C0V‐2 infection is transient in alveolar epithelial cells but persistent in endothelial cells. Administration of Tocilizumab, an anti‐IL6R antibody, does not prevent endothelial cell damage. In a human lung‐on‐chip model maintained at an air‐liquid interface exposed to SARS‐CoV‐2, endothelial lung microvascular cells are infected via alveolar epithelial cells, leading to persistent endothelial cell inflammation and loss of barrier integrity.