Integrin activation is an essential component of SARS-CoV-2 infection

Simons, Peter C.; Rinaldi, Derek A.; Bondu, Virginie; Kell, Alison; Bradfute, Steven B.; Lidke, Diane S.; Buranda, Tione

doi:10.1101/2021.07.20.453118

Cited by 6 publications

(6 citation statements)

References 72 publications

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“…The SARS-CoV-2 spike protein has been shown to bind multiple integrin subtypes. Although there is growing evidence for interactions based on the spike RGD sequence, the exact binding mechanisms are still unknown ( Robles et al, 2021 ; Simons et al, 2021 )⁠. Additionally, previous preliminary computational studies suggest that the spike RGD motif is not completely accessible for integrin-binding, while there have also been other non-RGD-binding integrins that have been suggested to be potentially involved in SARS-CoV-2 viral entry ( Othman et al, 2021 ; Wang et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Can the SARS-CoV-2 Spike Protein Bind Integrins Independent of the RGD Sequence?

Beaudoin

Hamaia

Huang

et al. 2021

Front. Cell. Infect. Microbiol.

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The RGD motif in the Severe Acute Syndrome Coronavirus 2 (SARS-CoV-2) spike protein has been predicted to bind RGD-recognizing integrins. Recent studies have shown that the spike protein does, indeed, interact with αVβ3 and α5β1 integrins, both of which bind to RGD-containing ligands. However, computational studies have suggested that binding between the spike RGD motif and integrins is not favourable, even when unfolding occurs after conformational changes induced by binding to the canonical host entry receptor, angiotensin-converting enzyme 2 (ACE2). Furthermore, non-RGD-binding integrins, such as αx, have been suggested to interact with the SARS-CoV-2 spike protein. Other viral pathogens, such as rotaviruses, have been recorded to bind integrins in an RGD-independent manner to initiate host cell entry. Thus, in order to consider the potential for the SARS-CoV-2 spike protein to bind integrins independent of the RGD sequence, we investigate several factors related to the involvement of integrins in SARS-CoV-2 infection. First, we review changes in integrin expression during SARS-CoV-2 infection to identify which integrins might be of interest. Then, all known non-RGD integrin-binding motifs are collected and mapped to the spike protein receptor-binding domain and analyzed for their 3D availability. Several integrin-binding motifs are shown to exhibit high sequence similarity with solvent accessible regions of the spike receptor-binding domain. Comparisons of these motifs with other betacoronavirus spike proteins, such as SARS-CoV and RaTG13, reveal that some have recently evolved while others are more conserved throughout phylogenetically similar betacoronaviruses. Interestingly, all of the potential integrin-binding motifs, including the RGD sequence, are conserved in one of the known pangolin coronavirus strains. Of note, the most recently recorded mutations in the spike protein receptor-binding domain were found outside of the putative integrin-binding sequences, although several mutations formed inside and close to one motif, in particular, may potentially enhance binding. These data suggest that the SARS-CoV-2 spike protein may interact with integrins independent of the RGD sequence and may help further explain how SARS-CoV-2 and other viruses can evolve to bind to integrins.

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Section: Discussionmentioning

confidence: 99%

Can the SARS-CoV-2 Spike Protein Bind Integrins Independent of the RGD Sequence?

Beaudoin

Hamaia

Huang

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Additional processes significantly enriched among severe mutations was ECM, whose importance in mediating the interaction with viral particles have been highlighted by affinity-purification proteomics experiments 25 . Recent experiments also confirmed a role for integrins in binding to UV-inactivated viral particles, through which outside-inside signaling is elicited via binding to Gα13 26 . Vesicle-mediated transport, such as clathrin-mediated endocytosis, has been shown to mediate a key entry point for SARS 27 .…”

Section: Respiratory or Thoracic Diseasementioning

confidence: 80%

An explainable model of host genetic interactions linked to COVID-19 severity

Onoja

Picchiotti²,

Fallerini³

et al. 2022

Commun Biol

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We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.

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“…Additional processes signi cantly enriched among severe mutations was ECM, whose importance in mediating the interaction with viral particles have been highlighted by a nitypuri cation proteomics experiments (Gordon et al, 2020). Recent experiments also con rmed a role for integrins in binding to UV-inactivated viral particles, through which outside-inside signaling is elicited via binding to Gα13 (Simons et al, 2021). Vesicle-mediated transport, such as clathrin-mediated endocytosis, has been shown to mediate a key entry point for SARS (Wang et al, 2008).…”

Section: Discussionmentioning

confidence: 95%

An explainable model of host genetic interactions linked to COVID-19 severity

Onoja

Picchiotti

Fallerini

et al. 2021

Preprint

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We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with training of multiple supervised classifiers, to predict severity on the basis of screened features. Feature importance analysis from decision-tree models allowed to identify a handful of 16 variants with highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with good accuracy (ACC=81.88%; ROC_AUC=96%; MCC=61.55%). Principal Component Analysis (PCA) and clustering of patients on important variants orthogonally identified two groups of individuals with a higher fraction of severe cases. Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response, such as JAK-STAT, Cytokine, Interleukin, and C-type lectin receptor signaling. It also identified additional processes cross-talking with immune pathways, such as GPCR signalling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits (e.g. “Respiratory or thoracic disease”), confirming their link with COVID-19 severity outcome. Taken together, our analysis suggests that curated genetic information can be effectively integrated along with other patient clinical covariates to forecast COVID-19 disease severity and dissect the underlying host genetic mechanisms for personalized medicine treatments.

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Integrin activation is an essential component of SARS-CoV-2 infection

Cited by 6 publications

References 72 publications

Can the SARS-CoV-2 Spike Protein Bind Integrins Independent of the RGD Sequence?

Can the SARS-CoV-2 Spike Protein Bind Integrins Independent of the RGD Sequence?

An explainable model of host genetic interactions linked to COVID-19 severity

An explainable model of host genetic interactions linked to COVID-19 severity

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