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Review 1: "Vimentin binds to SARS-CoV-2 spike protein and antibodies targeting extracellular vimentin block in vitro uptake of SARS-CoV-2 virus-like particles"

Reviewers: Dolores Pérez-Sala, María A. Pajares (Centro de Investigaciones Biológicas Margarita Salas) | 📒📒📒◻️◻️

Published onMay 05, 2022
Review 1: "Vimentin binds to SARS-CoV-2 spike protein and antibodies targeting extracellular vimentin block in vitro uptake of SARS-CoV-2 virus-like particles"
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Extracellular vimentin as a target against SARS-CoV-2 host cell invasion
Description

AbstractInfection of human cells by pathogens, including SARS-CoV-2, typically proceeds by cell surface binding to a crucial receptor. In the case of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) has been identified as a necessary receptor, but not all ACE2-expressing cells are equally infected, suggesting that other extracellular factors are involved in host cell invasion by SARS-CoV-2. 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. Here, we present evidence that extracellular vimentin might act as a critical component of the SARS-CoV-2 spike protein-ACE2 complex in mediating SARS-CoV-2 cell entry. We demonstrate direct binding between vimentin and SARS-CoV-2 pseudovirus coated with the SARS-CoV-2 spike protein and show that antibodies against vimentin block in vitro SARS-CoV-2 pseudovirus infection of ACE2-expressing cells. Our results suggest new therapeutic strategies for preventing and slowing SARS-CoV-2 infection, focusing on targeting cell host surface vimentin.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review:

The work by Suprewicz et al., explores the potential interaction of vimentin with the Spike protein from the SARS-CoV-2 virus in vitro. In addition, the ability of several anti-vimentin antibodies to block the binding/uptake of virus-like particles (VLP) containing Spike by cultured cells is evaluated. The authors employ a variety of approaches to inquire a wide spectrum of potential implications of vimentin in the interaction with SARS-CoV-2 including assessment of the interaction between recombinant vimentin and VLP-Spike in vitro by dynamic light scattering and atomic force microscopy; immunological detection of vimentin in samples from pulmonary tissue and on the surface of cultured cells; assessment of the effect of several anti-vimentin antibodies on the incorporation of VLP-Spike into ACE2-overexpressing epithelial cell lines, and molecular dynamics simulation of the potential effect of high-density cell-surface vimentin on the endocytosis of viral particles.

Taken together the results obtained point to an interaction of vimentin with Spike in vitro and to a negative effect of several anti-vimentin antibodies on the internalization of virus-like particles into cells in culture. Based on these findings the authors suggest general therapeutic strategies to prevent and reduce SARS-CoV-2 infection, consisting of the administration of anti-vimentin antibodies.

The results reported are encouraging and add interesting information on the complex role of vimentin in viral infections. However, in our opinion, the proposal of vimentin as a critical factor in SARS-CoV-2 infection and a useful therapeutic target will require additional work, including several essential controls for the current in vitro work, as well as data from in vivo models.

Some examples of control assays to strengthen the observations of the present work are given below:

-Assessment of several of the effects reported, including the cellular binding/uptake of VLP and the effects of blocking antibodies in vimentin KO cells.

-Evaluating the binding of vimentin to VLP lacking Spike or exposing another protein (VLP control). 

-Using an unrelated protein with characteristics similar to vimentin, instead of DNA, as a control for binding to VLP control and VLP-Spike.

-Assess the binding of VLP-Spike and VLP control to vimentin deficient cells treated or not with NETS, ideally containing or not vimentin.

-Assess the ability of Pritumumab to recognize extracellular vimentin in the cellular model employed.

-Since the manuscript proposes vimentin as a critical component of the Spike-ACE2 complex, provide some kind of evidence of a vimentin-ACE2-Spike interaction.

-Obtain experimental data on the real vimentin density on the cell membrane and its relationship to clathrin and Spike sites to support the interesting 3D-model of endocytosis proposed.

In summary, the manuscript presents very interesting work, but it alternates cautious statements with some claims that appear not sufficiently supported by the experimental evidence, or are speculative at this stage. In the urgency of the current pandemic situation, the manuscript provides numerous discrete pieces of evidence, not completely connected, but which will pave the way for future studies. Therefore, at this point, the study is not exempt from limitations that surely the authors are addressing, including the need for additional controls to confirm the role of vimentin in SARS-CoV-2 infection in cellular models. Moreover, additional in vivo experiments to support the main claims, above all those regarding the proposal of anti-vimentin antibodies as a therapy against COVID-19 will be required. Undoubtedly, the developments of this work will be of high interest. 

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