Vascular Protein Vimentin Assists SARS-CoV-2 Access Into Cells and Contributes To Vascular Complications

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A new study by researchers from Boston University School of Medicine has found that the human host vascular protein called Vimentin actually assists the SARS-CoV-2 coronavirus get access into cells and such actions can also contribute to vascular complications

The study findings were published in the peer reviewed journal: PNAS (Proceedings of the National Academy of Sciences of the United States of America) https://www.pnas.org/content/119/6/e2113874119

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) (1). SARS-CoV-2 binds to host receptors and attachment factors through its spike (S) glycoprotein and mediates membrane fusion and viral entry (2, 3).

Although infection of cells along the respiratory tract was almost immediately defined as an important hallmark of the disease, the SARS-CoV-2 virus has also been detected not only in the lungs, but also in the cardiovascular system, brain, liver, kidneys, and intestine (4⇓⇓–7). Angiotensin-converting enzyme 2 (ACE2) is recognized as an important receptor for SARS-CoV-2 (1, 2).

However, recent single-cell sequencing studies have demonstrated that ACE2 expression is relatively high in upper respiratory cells but low in the lower respiratory tract (8⇓⇓⇓–12), and this result coupled with the identification of multiple other factors—including AXL receptor tyrosine kinase (11), Neuropilin-1 (13), CD209L/L-SIGN, CD209/DC-SIGN (14), and heparin sulfate (15)—as additional potential receptors or coreceptors for SARS-CoV-2, suggest that multiple receptors/coreceptors may facilitate SARS-CoV-2 entry in a cell type-dependent manner. Therefore, variations in the mechanisms of SARS-CoV-2 entry could account for its robust tropism, transmission, and pathogenesis.

To search for unidentified receptors involved in SARS-CoV-2 entry into endothelial cells, we used SARS-CoV-2 S-receptor binding domain (S-RBD) as bait and whole-cell lysate (WCL) of human umbilical vein endothelial cells (HUVEC-TERT) as a source for prey proteins followed by liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis of proteins that showed an affinity for the SARS-CoV-2 S-RBD.

Our analysis identified vimentin (VIM) as a SARS-CoV-2 binding protein. Further biochemical and cell culture studies using pseudotyped viruses expressing SARS-CoV-2 S-protein or infectious SARS-CoV-2 demonstrated that VIM interacts with both SARS-CoV-2 S and ACE2 and acts as a coreceptor for SARS-CoV-2.

VIM is a type III intermediate filament protein and is widely expressed in cells of mesenchymal origin, such as endothelial cells, fibroblasts, and monocytes (16). In addition to its key role in intermediate filament formation, VIM is also present at the extracellular surface of endothelial cells and macrophages (17⇓–19).

Previous studies have found that extracellular VIM functions as an attachment factor or coreceptor for various viruses, including, SARS-CoV-1 (20), cowpea mosaic virus (21), Japanese encephalitis virus (22), dengue virus (23), and human papillomavirus (24). VIM could play an important role in promoting SARS-CoV-2 entry into the human vascular system, as well as other organs and tissues via cis- and trans-infection mechanisms.

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