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

Abstract

SARS-CoV-2 infection depends on binding its spike (S) protein to angiotensin-converting enzyme 2 (ACE2). The S protein expresses an RGD motif, suggesting that integrins may be co-receptors. Here, we UV-inactivated SARS-CoV-2 and fluorescently labeled the envelope membrane with octadecyl rhodamine B (R18) to explore the role of integrin activation in mediating cell entry and productive infection. We used flow cytometry and confocal microscopy to show that SARS-CoV-2R18 particles engage basal-state integrins. Furthermore, we demonstrate that Mn2+, which induces integrin extension, enhances cell entry of SARS-CoV-2R18. We also show that one class of integrin antagonist, which binds to the αI MIDAS site and stabilizes the inactive, closed conformation, selectively inhibits the engagement of SARS-CoV-2R18 with basal state integrins, but is ineffective against Mn2+-activated integrins. RGD-integrin antagonists inhibited SARS-CoV-2R18 binding regardless of integrin activation status. Integrins transmit signals bidirectionally: 'inside-out' signaling primes the ligand-binding function of integrins via a talin-dependent mechanism, and 'outside-in' signaling occurs downstream of integrin binding to macromolecular ligands. Outside-in signaling is mediated by Gα13. Using cell-permeable peptide inhibitors of talin and Gα13 binding to the cytoplasmic tail of an integrin's β subunit, we demonstrate that talin-mediated signaling is essential for productive infection.

• Authors: Peter Simons, Derek A Rinaldi, Virginie Bondu, Alison M Kell, Steven Bradfute, Diane S Lidke, Tione Buranda
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 20398 (10 14 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34650161 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021. The Author(s).

Chemical References

• Integrins

Topics

• Animals
• COVID-19 (metabolism)
• Chlorocebus aethiops
• Host-Pathogen Interactions
• Humans
• Integrins (metabolism)
• SARS-CoV-2 (physiology)
• Signal Transduction
• Vero Cells
• Virus Internalization