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

Authors

Peter Simons, Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA
Derek A. Rinaldi, Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA
Virginie Bondu, Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA
Alison M. Kell, Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USACenter for Infectious Diseases and Immunity, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA
Steven Bradfute, Center for Infectious Diseases and Immunity, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USADepartment of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA
Diane S. Lidke, Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA; Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA
Tione Buranda, Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA. tburanda@salud.unm.eduCenter for Infectious Diseases and Immunity, University of New Mexico School of Medicine, Albuquerque, NM

Document Type

Article

Publication Date

10-14-2021

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-2^R18 particles engage basal-state integrins. Furthermore, we demonstrate that Mn2+, which induces integrin extension, enhances cell entry of SARS-CoV-2^R18. 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-2^R18 with basal state integrins, but is ineffective against Mn²⁺-activated integrins. RGD-integrin antagonists inhibited SARS-CoV-2^R18 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.

Recommended Citation

Simons P, Rinaldi DA, Bondu V, Kell AM, Bradfute S, Lidke DS, Buranda T. Integrin activation is an essential component of SARS-CoV-2 infection. Sci Rep. 2021 Oct 14;11(1):20398. doi: 10.1038/s41598-021-99893-7. PMID: 34650161; PMCID: PMC8516859.