Direct activation of endothelial cells by SARS-CoV-2 nucleocapsid protein is blocked by Simvastatin

Abstract

Emerging evidence suggests that endothelial activation plays a central role in the pathogenesis of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. However, the molecular mechanisms underlying endothelial activation in COVID-19 patients remain unclear. In this study, the SARS-CoV-2 viral proteins that potently activate human endothelial cells were screened to elucidate the molecular mechanisms involved with endothelial activation. It was found that nucleocapsid protein (NP) of SARS-CoV-2 significantly activated human endothelial cells through TLR2/NF-κB and MAPK signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Remarkablely, though the protein sequences of N proteins from coronaviruses are highly conserved, only NP from SARS-CoV-2 induced endothelial activation. The NPs from other coronaviruses such as SARS-CoV, MERS-CoV, HUB1-CoV and influenza virus H1N1 did not affect endothelial activation. These findings are well consistent with the results from clinical investigations showing broad endotheliitis and organ injury in severe COVID-19 patients. In conclusion, the study provides insights on SARS-CoV-2-induced vasculopathy and coagulopathy, and suggests that simvastatin, an FDA-approved lipid-lowering drug, may benefit to prevent the pathogenesis and improve the outcome of COVID-19 patients.

Endothelial contribution to COVID-19: an update on mechanisms and therapeutic implications

“…1 E). Qian et al reported that the nucleocapsid (N) protein of SARS-CoV-2 was able to trigger endothelial inflammation by activating NFκB and MAPK signal pathway via TLR2 [ 67 ]. Altogether, these evidences have demonstrated the possibility of host cell entry or activation through expression of EC surface receptors; however, more work is needed to validate these findings in vivo .…”

Cell-Free Hemoglobin Does Not Attenuate the Effects of SARS-CoV-2 Spike Protein S1 Subunit in Pulmonary Endothelial Cells

“…A significant body of evidence indicates endothelial activation and pro-inflammatory cytokines play a critical role in the pathogenesis of the SARS-CoV-2 infection [19]. Additionally, a potential caveat to using HbA as a countermeasure for COVID-19-induced hypoxia is that hemoglobin has been reported to cause stimulation of IL-6, IL-8, and tumor necrosis factor-α from leukocytes in whole blood [20].…”

Viral Load and Patterns of SARS-CoV-2 Dissemination to the Lungs, Mediastinal Lymph Nodes, and Spleen of Patients with COVID-19 Associated Lymphopenia

“…The ultrastructural morphology of coronavirus particles we obtained by TEM examination of the tissue of the lungs and lymph nodes is similar to the data reported by other researchers, both in native tissues and in cell cultures [ 43 , 44 , 45 ]. The detection of SARS-CoV-2 virions in the cytoplasm of endothelial cells and its possible impact on the development of systemic pathology have been previously described by other authors [ 46 , 47 , 48 , 49 ]. The mechanism of lymphopenia due to the direct viral infection of T-lymphocytes and subsequent massive apoptosis has been described as related to the SARS-COV-2 coronaviruses MERS-CoV and SARS-CoV [ 29 , 30 , 31 ].…”