2 Results 2.1 Presence of Extracellular Vimentin in Human Lung, Airway Fluids, and Fat Tissue Our work highlights extracellular vimentin as a potential target against SARS-CoV-2 that could block the spread of COVID-19 and potentially other infectious diseases caused by viruses and bacteria that exploit cell surface vimentin for host invasion. Motivated by our experimental results, we present a novel coarse-grain model that captures the main features of membrane wrapping, treating extracellular vimentin as a co-receptor that mediates cell-virus interactions. We demonstrate that vimentin binds to SARS-CoV-2 pseudoviruses that are equipped with SARS-CoV-2 spike protein via dynamic light scattering (DLS) and atomic force microscopy (AFM) and propose a novel mechanism in which non-vimentin expressing cells can acquire vimentin released into the extracellular environment by neutrophil netosis. We show here that extracellular vimentin is also present in healthy adult lung tissue and detail the numerous routes by which it might arise in the lung, the respiratory tract, and other tissues. Interestingly, the expression of SARS-CoV-2 entry factors, ACE2 and transmembrane serine protease 2 (TMPRSS2), is particularly high in nasal epithelial goblet secretory cells and ciliated cells, on which immunohistological studies have shown the presence of vimentin. While cell surface vimentin is an unconventional target for viruses, there are now numerous studies implicating its role in the binding and uptake of multiple different viruses, including the SARS-CoV virus, suggesting it might also be involved in cell host invasion by SARS-CoV-2. Here, we report that cell surface vimentin acts as a co-receptor for SARS-CoV-2 host cell invasion and that antibodies against vimentin can block up to 80% of the cellular uptake of SARS-CoV-2 pseudovirus. The ongoing coronavirus disease 2019 (COVID-19) pandemic and the threat of future coronavirus outbreaks underscore the need to identify the precise entry mechanism used by the SARS-CoV-2 virus to develop protective strategies against it. These findings have given rise to an emerging hypothesis of a critical co-receptor that facilitates binding of the SARS-CoV-2 virus and its delivery to ACE2, and several possible SARS-CoV-2 co-receptor candidates have been found, including neuropilins, heparan sulfate, and sialic acids. At the super-physiological concentrations above n m used in vitro, the half time of maximal binding for SARS-CoV-2 is around 30 s, and the concentration in vivo is substantially lower. The expression of ACE2 in the human respiratory system is low compared to other organs and while the affinity of the SARS-CoV-2 spike protein with ACE is especially strong, the binding-on rate is slow. While ACE2 is required for SARS-CoV and SARS-CoV-2 infection, it does not appear solely sufficient. The ACE2 receptor is expressed in a plethora of tissues, including the lung, kidney, gastrointestinal tract, and vascular endothelium, which all serve as sites for SARS-CoV-2 infection. The SARS-CoV-2 virus is genetically similar to SARS-CoV (SARS) and uses the SARS-CoV receptor, angiotensin-converting enzyme 2 (ACE2), for cell entry. Infection of human cells by pathogens, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), proceeds by a series of cell surface protein binding and membrane fusion events that are usually centered on a crucial receptor. Extracellular vimentin may thus serve as a critical component of the SARS-CoV-2 spike protein-ACE2 complex in mediating SARS-CoV-2 cell entry, and vimentin-targeting agents may yield new therapeutic strategies for preventing and slowing SARS-CoV-2 infection. The results are consistent with a model in which extracellular vimentin acts as a co-receptor for SARS-CoV-2 spike protein with a binding affinity less than that of the spike protein with ACE2. ![]() ![]() Dynamic light scattering shows that vimentin binds to pseudovirus coated with the SARS-CoV-2 spike protein, and antibodies against vimentin block in vitro SARS-CoV-2 pseudovirus infection of ACE2-expressing cells. Biophysical and cell infection studies are done to determine whether vimentin might bind SARS-CoV-2 and facilitate its uptake. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens’ cellular uptake. The primary receptor for SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2), yet new studies reveal the importance of additional extracellular co-receptors that mediate binding and host cell invasion by SARS-CoV-2. Infection of human cells by pathogens, including SARS-CoV-2, typically proceeds by cell surface binding to a crucial receptor.
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