SARS-CoV-2 Infects Human ACE2-Negative Endothelial Cells through an α v β 3 Integrin-Mediated Endocytosis Even in the Presence of Vaccine-Elicited Neutralizing Antibodies.
Antonella BugattiFederica FilippiniMarta BardelliAlberto ZaniPaola ChiodelliSerena MessaliArnaldo CarusoFrancesca CaccuriPublished in: Viruses (2022)
Integrins represent a gateway of entry for many viruses and the Arg-Gly-Asp (RGD) motif is the smallest sequence necessary for proteins to bind integrins. All Severe Acute Respiratory Syndrome Virus type 2 (SARS-CoV-2) lineages own an RGD motif (aa 403-405) in their receptor binding domain (RBD). We recently showed that SARS-CoV-2 gains access into primary human lung microvascular endothelial cells (HL-mECs) lacking Angiotensin-converting enzyme 2 (ACE2) expression through this conserved RGD motif. Following its entry, SARS-CoV-2 remodels cell phenotype and promotes angiogenesis in the absence of productive viral replication. Here, we highlight the α v β 3 integrin as the main molecule responsible for SARS-CoV-2 infection of HL-mECs via a clathrin-dependent endocytosis. Indeed, pretreatment of virus with α v β 3 integrin or pretreatment of cells with a monoclonal antibody against α v β 3 integrin was found to inhibit SARS-CoV-2 entry into HL-mECs. Surprisingly, the anti-Spike antibodies evoked by vaccination were neither able to impair Spike/integrin interaction nor to prevent SARS-CoV-2 entry into HL-mECs. Our data highlight the RGD motif in the Spike protein as a functional constraint aimed to maintain the interaction of the viral envelope with integrins. At the same time, our evidences call for the need of intervention strategies aimed to neutralize the SARS-CoV-2 integrin-mediated infection of ACE2-negative cells in the vaccine era.
Keyphrases
- sars cov
- endothelial cells
- respiratory syndrome coronavirus
- angiotensin converting enzyme
- angiotensin ii
- induced apoptosis
- monoclonal antibody
- randomized controlled trial
- cell adhesion
- cell migration
- poor prognosis
- cell cycle arrest
- stem cells
- transcription factor
- machine learning
- high glucose
- electronic health record
- amino acid
- bone marrow
- big data
- coronavirus disease
- cell proliferation
- zika virus
- long non coding rna
- data analysis
- induced pluripotent stem cells
- protein protein
- pluripotent stem cells