Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.10.243220v1?rss=1 Authors: Thacker, V. V., Sharma, K., Dhar, N., Mancini, G.-F., Sordet-Dessimoz, J., Mckinney, J. D. Abstract: BackgroundSevere manifestations of COVID-19 include hypercoagulopathies and systemic endothelialitis. The underlying dynamics of damage to the vasculature, and whether it is a direct consequence of endothelial infection or an indirect consequence of immune cell mediated cytokine storms is unknown. This is in part because in vitro infection models are typically monocultures of epithelial cells or fail to recapitulate vascular physiology. MethodsWe establish a vascularised lung-on-chip infection model consisting of a co-culture of primary human alveolar epithelial cells ( epithelial) and human lung microvascular endothelial cells ( endothelial), with the optional addition of CD14+ macrophages to the epithelial side. A combination of qRT-PCR, RNAscope, immunofluorescence, and ELISA measurements are used to study the dynamics of viral replication and host responses to a low dose infection of SARS-CoV-2 delivered to the apical surface of the epithelial face maintained at an air-liquid interface. FindingsSARS-CoV-2 inoculation does not lead to a productive amplification of infectious virions. However, both genomic and antisense viral RNA can be found in endothelial cells within 1-day post infection (dpi) and persist upto 3 dpi. This generates an NF-KB inflammatory response typified by IL-6 secretion and a weak antiviral interferon response even in the absence of immune cells. Endothelial inflammation leads to a progressive loss of barrier integrity, a subset of cells also shows a transient hyperplasic phenotype. Administration of Tocilizumab slows the loss of barrier integrity but does not reduce the occurrence of the latter. InterpretationEndothelial infection can occur through basolateral transmission from infected epithelial cells at the air-liquid interface. SARS-CoV-2 mediated inflammation occurs despite the lack of rapid viral replication and the consequences are cell-type dependent. Infected endothelial cells might be a key source of circulating IL-6 in COVID-19 patients. Vascular damage occurs independently of immune-cell mediated cytokine storms, whose effect would only exacerbate the damage. FindingCore support from EPEL. Copy rights belong to original authors. Visit the link for more info