Integrin mediates cell entry of the SARS-CoV-2 virus independent of cellular receptor ACE2

Abstract

Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is broadly accepted that SARS-CoV-2 utilizes its spike protein to recognize the extracellular domain of angiotensin-converting enzyme 2 (ACE2) to enter cells for viral infection. However, other mechanisms of SARS-CoV-2 cell entry may occur. We show quantitatively that the SARS-CoV-2 spike protein also binds to the extracellular domain of broadly expressed integrin α5β1 with an affinity comparable to that of SARS-CoV-2 binding to ACE2. More importantly, we provide direct evidence that such binding promotes the internalization of SARS-CoV-2 into non-ACE2 cells in a manner critically dependent upon the activation of the integrin. Our data demonstrate an alternative pathway for the cell entry of SARS-CoV-2, suggesting that upon initial ACE2-mediated invasion of the virus in the respiratory system, which is known to trigger an immune response and secretion of cytokines to activate integrin, the integrin-mediated cell invasion of SARS-CoV-2 into the respiratory system and other organs becomes effective, thereby promoting further infection and progression of COVID-19. Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is broadly accepted that SARS-CoV-2 utilizes its spike protein to recognize the extracellular domain of angiotensin-converting enzyme 2 (ACE2) to enter cells for viral infection. However, other mechanisms of SARS-CoV-2 cell entry may occur. We show quantitatively that the SARS-CoV-2 spike protein also binds to the extracellular domain of broadly expressed integrin α5β1 with an affinity comparable to that of SARS-CoV-2 binding to ACE2. More importantly, we provide direct evidence that such binding promotes the internalization of SARS-CoV-2 into non-ACE2 cells in a manner critically dependent upon the activation of the integrin. Our data demonstrate an alternative pathway for the cell entry of SARS-CoV-2, suggesting that upon initial ACE2-mediated invasion of the virus in the respiratory system, which is known to trigger an immune response and secretion of cytokines to activate integrin, the integrin-mediated cell invasion of SARS-CoV-2 into the respiratory system and other organs becomes effective, thereby promoting further infection and progression of COVID-19. The coronavirus disease 2019 (COVID-19)–induced global pandemic has been ongoing for nearly 2 years causing >350 million infections. Although the massive vaccination effort at global scale has reduced the severe threat of the COVID-19 pandemic, the mortality rate remains still relatively high (from ∼5% in the beginning of pandemic to ∼2% now) with a total of >5.5 million deaths. The pathogen causing this disastrous disease is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that belongs to the family of coronaviruses including 229E, NL63, OC43, HKU1, MERS-CoV, and highly homologous SARS-CoV (1Zhou P. Yang X.L. Wang X.G. Hu B. Zhang L. Zhang W. Si H.R. Zhu Y. Li B. Huang C.L. Chen H.D. Chen J. Luo Y. Guo H. Jiang R.D. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579: 270-273Google Scholar). However, SARS-CoV-2 is apparently much more contagious than any other coronaviruses, and the mechanism underlying its infectivity is not well understood. Each SARS-CoV-2 is ∼50 to 200 nm in diameter containing an RNA segment of 30,000 bases encoding the virus, four structural proteins, the spike, envelop, membrane, and nucleocapsid proteins. The nucleocapsid protein holds the RNA genome, whereas other proteins form the viral envelope (2Wrapp D. Wang N. Corbett K.S. Goldsmith J.A. Hsieh C.-L. Abiona O. Graham B.S. McLellan J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.bioRxiv. 2020; ([preprint])https://doi.org/10.1101/2020.02.11.944462Google Scholar). The spike protein contains 1273 amino acids that are divided into S1 domain (1–541), a linker (542–685), S2 domain (686–1213), a single-pass transmembrane segment (1214–1236), and a short cytoplasmic tail (1237–1273) (3Lan J. Ge J. Yu J. Shan S. Zhou H. Fan S. Zhang Q. Shi X. Wang Q. Zhang L. Wang X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.Nature. 2020; 581: 215-220Google Scholar, 4Wang Q. Zhang Y. Wu L. Niu S. Song C. Zhang Z. Lu G. Qiao C. Hu Y. Yuen K.Y. Wang Q. Zhou H. Yan J. Qi J. Structural and functional basis of SARS-CoV-2 entry by using human ACE2.Cell. 2020; 181: 894-904.e9Google Scholar). Importantly, S1 utilizes a fragment (333–529) called its receptor binding domain (RBD) to recognize angiotensin-converting enzyme 2 (ACE2)—a minor variant of ACE (5Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.Circ. Res. 2000; 87: E1-E9Google Scholar) to initiate virus entry and infection (2Wrapp D. Wang N. Corbett K.S. Goldsmith J.A. Hsieh C.-L. Abiona O. Graham B.S. McLellan J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.bioRxiv. 2020; ([preprint])https://doi.org/10.1101/2020.02.11.944462Google Scholar, 4Wang Q. Zhang Y. Wu L. Niu S. Song C. Zhang Z. Lu G. Qiao C. Hu Y. Yuen K.Y. Wang Q. Zhou H. Yan J. Qi J. Structural and functional basis of SARS-CoV-2 entry by using human ACE2.Cell. 2020; 181: 894-904.e9Google Scholar). Such ACE2-mediated virus entry was first found for the homologous SARS-CoV in 2003 (6Li W. Moore M.J. Vasilieva N. Sui J. Wong S.K. Berne M.A. Somasundaran M. Sullivan J.L. Luzuriaga K. Greenough T.C. Choe H. Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Nature. 2003; 426: 450-454Google Scholar), although SARS-CoV only caused ∼8000 infections and did not lead to global pandemic. ACE2 contains an N-terminal peptidase domain and a C-terminal collectrin renal amino acid transporter domain on its extracellular region, followed by a single-pass transmembrane domain and a small intracellular domain (4Wang Q. Zhang Y. Wu L. Niu S. Song C. Zhang Z. Lu G. Qiao C. Hu Y. Yuen K.Y. Wang Q. Zhou H. Yan J. Qi J. Structural and functional basis of SARS-CoV-2 entry by using human ACE2.Cell. 2020; 181: 894-904.e9Google Scholar). ACE2’s major physiological role is to lower blood pressure by using the peptidase domain to hydrolyze angiotensin II (a vasoconstrictor hormone peptide) into angiotensin 1 to 7 (a vasodilator). The SARS-CoV-2 S1 RBD binding to ACE2 does not affect the activity of ACE2 but rather promotes the attachment of the virus onto the cell surface. The virus attachment is followed by a furin-mediated cleavage at its S1/S2 site to facilitate the entry of SARS-CoV-2 into cells (7Hoffmann M. Kleine-Weber H. Schroeder S. Krüger N. Herrler T. Erichsen S. Schiergens T.S. Herrler G. Wu N.H. Nitsche A. Müller M.A. Drosten C. Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280.e8Google Scholar), which ultimately lead to the replication of the virus and its release via exocytosis to infect more cells. While this ACE2-mediated SARS-CoV-2 cell entry is widely accepted, the mechanism underlying the progression of the virus infection and the heterogeneous severity (asymptomatic, lightly symptomatic to severe, critical, or even lethal conditions) (8Buszko M. A. D. on the role of cytokines in Scholar) remains understood. was that the of cytokines the the symptomatic of cytokines Shi Li Q. J. Hu J.L. W. Zhang Y. K. Zhang F. J. Wu B. et and of SARS-CoV-2 2020; Scholar). It is that COVID-19 of cytokines or J. Scholar) via that by the virus infection in the respiratory More importantly, that SARS-CoV-2 only infection severe disease progression in human ACE2 but the SARS-CoV-2 infection to other organs in to in an Chen R.E. F. S. M.J. A. M. SARS-CoV-2 infection severe disease in human ACE2 Scholar). that although ACE2 is for the initial invasion of SARS-CoV-2, is highly that mechanisms for promoting further progression of SARS-CoV-2 infection. proteins such and in cells been to with ACE2 to the virus infection of in SARS-CoV-2 Scholar), but and SARS-CoV-2 non-ACE2 cells that may the progression of COVID-19 is using Chen Q. Yang G. Wang Huang Zhang Li R. Guo Y. Huang Q. et al.A of SARS-CoV-2 infection and 2020; Scholar) and human COVID-19 T. Y. M.A. Wang S. D. J. M. of SARS-CoV-2 for human Scholar, F. A. A. A. D. E. F. S. P. G. S. F. P. A. SARS-CoV-2 infection the and promotes of human Scholar, D. S. S. A. M. C. J. K. A. P. M. S. et infection and the human and Scholar) that SARS-CoV-2 not only cells but also non-ACE2 suggesting the of entry mechanism for and that SARS-CoV-2 RBD contains a acid that is in other coronaviruses A. P. A role for in cell entry by Res. 2020; Scholar, L. W. J. and of integrin binding via a in the SARS spike Scholar, N. W. Hu The integrin binding a novel for SARS-CoV-2 Scholar). Such is known to by of a family of cell which are transmembrane proteins containing extracellular transmembrane and small cytoplasmic tail Scholar). to recognize containing such and disease virus, and cell entry via integrin-mediated The to Scholar). and been to may SARS-CoV-2 and the of the virus F. A. A. A. D. E. F. S. P. G. S. F. P. A. SARS-CoV-2 infection the and promotes of human Scholar, A. P. A role for in cell entry by Res. 2020; Scholar, L. W. J. and of integrin binding via a in the SARS spike Scholar, S. S. A. E. E. A. M. The spike of SARS-CoV-2 binds to expressed on the of Scholar, S. Lu Y. J. Zhang L. rate of in COVID-19 is to Scholar, D. N. SARS-CoV-2 major integrin to Scholar, S. H. X. G. for role for in SARS-CoV-2 and for virus 2020; Scholar, P. S. T. activation is an of SARS-CoV-2 Scholar). However, of role of in SARS-CoV-2 has been to the SARS-CoV-2 binding to integrin in to ACE2. the mechanism of integrin on SARS-CoV-2 in to ACE2 remains highly and a of that integrin with ACE2 to the SARS-CoV-2 infection whereas that integrin the SARS-CoV-2 binding to ACE2 S. Lu Y. J. Zhang L. rate of in COVID-19 is to Scholar, J. Lu Y. S. Zhang L. A role for integrin in the receptor of 2020; Scholar). the of integrin activation for the SARS-CoV-2 infection P. S. T. activation is an of SARS-CoV-2 Scholar) but other L. W. J. and of integrin binding via a in the SARS spike Scholar, The to Scholar, S. S. A. E. E. A. M. The spike of SARS-CoV-2 binds to expressed on the of Scholar, S. Lu Y. J. Zhang L. rate of in COVID-19 is to Scholar, D. N. SARS-CoV-2 major integrin to Scholar) did not show such The on cells that integrin and ACE2 which to the of the integrin the of the integrin which and to cell may also to the of the we a of and with non-ACE2 cells to the role of the integrin-mediated cell entry of and we show that SARS-CoV-2 spike protein binds to widely integrin α5β1 with an affinity that is comparable to that SARS-CoV-2 and ACE2. We further demonstrate that such binding to the internalization of SARS-CoV-2 into non-ACE2 cells in a manner that is critically dependent on the activation of integrin, its to a for Our data provide evidence for an alternative pathway of SARS-CoV-2 entry into cells. that initial SARS-CoV-2 infection via ACE2 in the respiratory system is known to cytokines F. L. L. F. M. The in of the of the 2020; Scholar) that activate A. The role of in and Res. Scholar, X. D. promotes and in the cell 2000; Scholar, D. C.L. A. Wang X. a and the integrin Scholar), data that more SARS-CoV-2 may enter into the human cells and ACE2 thereby to further infection and progression of COVID-19. Our may in the global pandemic of COVID-19. the binding of integrin to SARS-CoV-2 F. A. A. A. D. E. F. S. P. G. S. F. P. A. SARS-CoV-2 infection the and promotes of human Scholar, A. P. A role for in cell entry by Res. 2020; Scholar, N. W. Hu The integrin binding a novel for SARS-CoV-2 Scholar, S. S. A. E. E. A. M. The spike of SARS-CoV-2 binds to expressed on the of Scholar, S. Lu Y. J. Zhang L. rate of in COVID-19 is to Scholar, D. N. SARS-CoV-2 major integrin to Scholar, S. H. X. G. for role for in SARS-CoV-2 and for virus 2020; Scholar, P. S. T. activation is an of SARS-CoV-2 Scholar, J. Lu Y. S. Zhang L. A role for integrin in the receptor of 2020; Scholar), and has been to the binding the SARS-CoV-2 and integrin, we first the using SARS-CoV-2 RBD and extracellular domain of integrin a receptor that is broadly in and blood cells. that SARS-CoV-2 RBD binding to We which the binding affinity SARS-CoV-2 RBD and integrin at affinity is in the that SARS-CoV-2 spike protein and ACE2 which was J. C.L. A. Wang X. Structural basis of receptor by 2020; 581: Scholar). that to on the SARS-CoV-2 RBD its binding to integrin, further the of the binding and the of in SARS-CoV-2 RBD in of integrin. further the of SARS-CoV-2 RBD with integrin, we to to the of RBD with cells. is a cell containing α5β1 N. C. L. D. R. A. A novel protein to by integrin in and in Scholar, X. H. S. Z. X. Chen W. M. Wang W. S. N. B. W. Fan et of the cell Scholar). The cell was and has ACE2 (5Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.Circ. Res. 2000; 87: E1-E9Google Scholar) the has ACE2 (5Donoghue M. Hsieh F. Baronas E. Godbout K. Gosselin M. Stagliano N. Donovan M. Woolf B. Robison K. Jeyaseelan R. Breitbart R.E. Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.Circ. Res. 2000; 87: E1-E9Google Scholar). the of using cell that integrin and ACE2 and is to evidence of the However, first to by cells not that RBD has with on the cell surface. in cells in that for binding Scholar), we the cells using a integrin H. Li A. N. J.A. activation by or a and of a novel site on the integrin Scholar, S. D. K. J. C. N. Structural into integrin by Scholar, J. C. E. K. D. D. Z. S. M. R. J. et envelope protein binds to and integrin the receptor for Scholar, T. T. T. D. G. is an receptor for Scholar). The the by the of with cells that activation of integrin to binding to RBD on cell surface. may to integrin the SARS-CoV-2 R. J. M. J. P. J. L. B. K. K. et for SARS-CoV-2 and Scholar, Z. S. M. S. Lu L. E. O. H. P. T. et of for SARS-CoV-2 infection in human Scholar, J. R.E. Zhang Chen J.S. et for SARS-CoV-2 Scholar) integrin in the may been in an We that RBD with integrin α5β1 in and is in the of such and integrin known to the of the receptor Scholar), the to by in total high affinity to to α5β1 at any J. Y. W. Y. M.J. D. C. Lu C. and integrin J. Scholar). affinity is comparable to that of the α5β1 is lower than α5β1 of Li et J. Y. W. Y. M.J. D. C. Lu C. and integrin J. The affinity of receptor is to the of cell and any α5β1 in a and which binds to at than the receptor at which may N. W. Hu The integrin binding a novel for SARS-CoV-2 Scholar, S. S. A. E. E. A. M. The spike of SARS-CoV-2 binds to expressed on the of Scholar) the SARS-CoV-2 spike binding to integrin is with a that activation of integrin is for its binding to SARS-CoV-2 P. S. T. activation is an of SARS-CoV-2 Scholar) and also with that activation of is for binding to such J. C. E. K. D. D. Z. S. M. R. J. et envelope protein binds to and integrin the receptor for Scholar) but is not for small such disease virus A. Wang Q. X. M. R. J. B. of integrin and disease Scholar) is also further that the of RBD with cells is dependent on integrin but not on other such or a of other that the spike protein has been to we the RBD binding using to the and also that binding of to and α5β1 F. S. R. J. C. J. B. H. A of the activity and of for Scholar). the RBD binding to the integrin α5β1 extracellular However, we to the binding using in the of any not et Li A. of the of the internalization and the of viral containing or Scholar) that in did not affect the virus attachment but reduced the virus to RBD is upon binding to the integrin, which the binding and this we the cell by cells first with RBD this we only at the protein attachment the internalization of that reduced of RBD with and also RBD with that RBD binds to integrin on the cell surface. we to SARS-CoV-2 RBD into cells by binding to integrin α5β1 we this that SARS-CoV-2 enter non-ACE2 cells the of integrin is well known to into via The to Scholar, M.A. C. new for Scholar). also but may integrin and in integrin to the cell A. J. S. J. of and Scholar). Although the is to the cell entry of SARS-CoV via ACE2 evidence that SARS-CoV also via an H. Yang P. K. Guo F. Zhang Y. Zhang G. Jiang C. SARS coronavirus entry into cells a novel and Res. Scholar). It is that of of on which is of that RBD into cells but not in cells the activation of integrin is for internalization of RBD into which is with the data of RBD binding to integrin α5β1 We also integrin to the cell of the cell Importantly, reduced the that RBD is the with the integrin We also cells with and show that RBD Our provide evidence that SARS-CoV-2 RBD into cells binding to integrin α5β1 in such human disease virus, human to into cells via integrin The to Scholar) and integrin α5β1 highly the to the entry of SARS-CoV-2 via integrin to using a we not to we to the a and to of virus infection such virus attachment and cell also been to COVID-19 such COVID-19 that is a we with SARS-CoV-2 spike proteins D. O. Chen J. P. of the coronavirus ACE2 of viral attachment and entry for Scholar, D. O. P. the SARS-CoV-2 mechanism that to its activity 2020; Scholar, A. Y. C. Graham by in cells its role in activation and SARS-CoV-2 viral Scholar) to infect cells and cells. this a that the protein in the cell virus we also cells with integrin to show the cell that the cells in the of and the cell entry is critically dependent on the activation of integrin by of cells although a lead to even infection rate not the entry of the was by rate reduced to with the entry demonstrate that the cell entry of SARS-CoV-2 by integrin in non-ACE2 of or other that the spike protein has been to this is the first direct evidence the cell entry of the SARS-CoV-2 in non-ACE2 cells. integrin or with ACE2 to the SARS-CoV-2 we expressed in cells. with of SARS-CoV-2 entry integrin activation by that of the high of SARS-CoV-2 that the cell entry of upon to activate integrin, the SARS-CoV-2 entry was in the whereas the of integrin by the cell entry of the virus apparently the integrin is by that the entry not with are and other are expressed on the cell with integrin also that integrin still to SARS-CoV-2 spike protein or RBD in the of with reduced A and to the integrin and ACE2 binding to the SARS-CoV-2 site is to the ACE2 site on RBD A. P. A role for in cell entry by Res. 2020; Scholar, J. Lu Y. S. Zhang L. A role for integrin in the receptor of 2020; Scholar). is integrin and ACE2 the that the or with other via direct However, ACE2 and integrin to spike proteins of the SARS-CoV-2 ACE2 (7Hoffmann M. Kleine-Weber H. Schroeder S. Krüger N. Herrler T. Erichsen S. Schiergens T.S. Herrler G. Wu N.H. Nitsche A. Müller M.A. Drosten C. Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280.e8Google Scholar) and integrin Scholar, F. S. R. J. C. J. B. H. A of the activity and of for Scholar) and to the virus such binding may the virus entry in the virus enter the cell via at the human cells containing ACE2 and integrin also found to to SARS-CoV-2 of et M. J.L. M.J. R. K. Z. H. N. K. et of SARS-CoV-2 infection of an human It was also S. Lu Y. J. Zhang L. rate of in COVID-19 is to Scholar) that integrin and expressed on cells other for the virus binding and infection. to the data cells that found to to the SARS-CoV-2 infection and by integrin N. W. Hu The integrin binding a novel for SARS-CoV-2 Scholar, P. S. T. activation is an of SARS-CoV-2 Scholar). that human cells to SARS-CoV-2 on that are not understood. The of ACE2 and integrin and in cells containing may a role in the virus infection. The mechanism to and cells containing ACE2 and integrin to SARS-CoV-2 remains to further using non-ACE2 cells demonstrate that integrin α5β1 of ACE2 to the SARS-CoV-2 Although SARS-CoV-2 has been the global pandemic its high and high rate to still understood. The infection in respiratory system but further to severe, critical, or even lethal remains we provide evidence that in to binding to receptor SARS-CoV-2 spike protein also with integrin with an affinity that is comparable to that SARS-CoV-2 and ACE2. More importantly, we demonstrate that SARS-CoV-2 cells upon binding to integrin and such infection is ACE2 The infection to also other that the spike protein has been to we the and The of integrin activation to to SARS-CoV-2 to integrin the SARS-CoV-2 R. J. M. J. P. J. L. B. K. K. et for SARS-CoV-2 and Scholar, Z. S. M. S. Lu L. E. O. H. P. T. et of for SARS-CoV-2 infection in human Scholar, J. R.E. Zhang Chen J.S. et for SARS-CoV-2 Scholar), integrin in the is apparently in Our that ACE2-mediated SARS-CoV-2 invasion a role in the infection in the respiratory system, activation of binding such α5β1 may further to infection by binding and virus into more cells and non-ACE2 containing The is with the of SARS-CoV-2 in non-ACE2 cells of Chen Q. Yang G. Wang Huang Zhang Li R. Guo Y. Huang Q. et al.A of SARS-CoV-2 infection and 2020; Scholar), M. J.L. M.J. R. K. Z. H. N. K. et of SARS-CoV-2 infection of an human Scholar), T. Y. M.A. Wang S. D. J. M. of SARS-CoV-2 for human Scholar), and of COVID-19 F. A. A. A. D. E. F. S. P. G. S. F. P. A. SARS-CoV-2 infection the and promotes of human Scholar, D. S. S. A. M. C. J. K. A. P. M. S. et infection and the human and Scholar). A is and are to the SARS-CoV-2 infection in with the ACE2 we although are highly that are in the with a binding The of integrin is even for cell that are to the such in the respiratory a small of bound to and for virus activate integrin, a of by cytokines A. The role of in and Res. Scholar, X. D. promotes and in the cell 2000; Scholar, D. C.L. A. Wang X. a and the integrin Scholar) or other may on integrin cytoplasmic causing of the receptor Scholar). Such integrin an entry receptor for the other although the of ACE2 is and in in the respiratory system to the ACE2 is to the viral on this and we to the progression of SARS-CoV-2 first ACE2 in the respiratory system to trigger the initial virus infection. The SARS-CoV-2 infection and of cytokines to the respiratory system and other of the which in trigger to activate binding on cells non-ACE2 causing more entry and massive replication of the virus in and which ultimately to the of the such severe infection and Such of ACE2 and integrin-mediated virus is mechanism to to high and high rate of SARS-CoV-2 in the disease ACE2 cell infection release integrin activation non-ACE2 cell infection more release more integrin activation more non-ACE2 cell infection severe is of infections that the immune response and the immune cells. the of Shi Li Q. J. Hu J.L. W. Zhang Y. K. Zhang F. J. Wu B. et and of SARS-CoV-2 2020; Scholar) and the of the Chen R.E. F. S. M.J. A. M. SARS-CoV-2 infection severe disease in human ACE2 Scholar), well the integrin activation may the SARS-CoV-2 the severe SARS-CoV-2 RBD was into RBD protein was cells. The cells in with for cells to to was using was by containing was was to and was and to at using a and with binding with binding and to 200 with for was by RBD and RBD using RBD was with SARS-CoV-2 SARS-CoV-2 SARS-CoV-2 RBD and integrin α5β1 extracellular domain with on and on The of proteins was on with 200 1 The for at and with of The of integrin was into and for at and with of in and onto The integrin α5β1 was by ACE2 was by and proteins by on the at and was onto The was at and in 200 1 by using binding and by cells with and at 1 cells in in the and of 1 in the and of for at that the the in that is known to proteins. at for and in in and with RBD 1 cells in for at and in The of RBD with cells was by in cell for RBD cells first with RBD in the and of 1 and in the and of for at and in cells data not cells on a with 1 with and for cells the and on for and with containing RBD protein and integrin in with in the and of 1 in the or of on for 1 and at for the cells on for and with with for at with and with the and on with with in at using the SARS-CoV-2 was to the with minor an by cells on a with 1 with and for was using cell to to cells for was cells with and with A of of 2 with with and 1 with and was onto cells. The was at for at cells at for followed by with further at for to with with with integrin followed by and on with with by at at using was and which for to the and cell using the cells with the for The of infection was by the of cells by the of cells. the data are the and its contains The that of with the of this We by for cell and for on data We also for J. L. and J. Q. J. F. and Y. C. J. L. and J. Q. F. E. and J. Q. and J. Q. The was by the of to J. and to E. P. and J. and to J. L. The is the of the and does not the of the of

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