CXCL10-dependent epithelial-vascular cross-talk for endothelial activation following Sars-CoV-2 infection

Abstract

Abstract The vasculature is heavily impacted by SARS-CoV-2 infection. Conflicting results exist about the mechanisms by which SARS-CoV-2 virus acts on the vasculature. The presence of the virus within endothelial cells has been reported in patients’ samples. However, the ACE2 receptor is not detected in endothelial cells when analyzed by RNAseq analysis. Thus, it is not clear how SARS-CoV-2 is contributing to vascular inflammation and whether a cross-talk between epithelial cells and endothelial cells is involved. We, therefore, investigated the interaction between SARS-CoV-2 and the vasculature using 2D and 3D in vitro models including our previously developed 3D vesseloid model. We first determined the suitability of the 3D vesseloid model for our study and then assessed whether SARS-CoV-2 is able to directly infect endothelial cells. In the absence of ACE2 in endothelial cells, no infection could be detected. When ACE2 was overexpressed in endothelial cells, a low uptake of viral particles in endothelial cells has been observed without efficient viral production. We then explored the possibility of an indirect effect of SARS-CoV-2 infection involving an epithelial-endothelial cells cross-talk. After infection of epithelial cells, a significant inflammatory response was detected in endothelial cells. Furthermore, we investigated the cytokines possibly implicated and identified CXCL10 as the most expressed pro-inflammatory cytokine and explored its function in this context. Finally, clinical relevance of our findings was confirmed by CXCL10 and alternative cytokines dosage in blood samples of Sars-CoV-2 infected patients, and validated in silico in an independent patient’s cohort.