Diverse roles of SARS-CoV-2 Spike and Nucleocapsid proteins in EndMT stimulation through the TGF-β-MRTF axis inhibited by aspirin

{ 'indexed': {'date-parts': [[2024, 5, 28]], 'date-time': '2024-05-28T17:40:18Z', 'timestamp': 1716918018065}, 'reference-count': 73, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2024, 5, 28]], 'date-time': '2024-05-28T00:00:00Z', 'timestamp': 1716854400000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2024, 5, 28]], 'date-time': '2024-05-28T00:00:00Z', 'timestamp': 1716854400000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'funder': [ { 'DOI': '10.13039/501100004281', 'name': 'Narodowe Centrum Nauki', 'doi-asserted-by': 'publisher', 'award': ['2017/01/X/NZ7/00499', '2017/01/X/NZ7/00499']}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'abstract': '<jats:title>Abstract</jats:title><jats:sec>\n' ' <jats:title>Background</jats:title>\n' ' <jats:p>The SARS-CoV-2 virus causes severe COVID-19 in one-fifth of patients. ' 'In addition to high mortality, infection may induce respiratory failure and cardiovascular ' 'complications associated with inflammation. Acute or prolonged inflammation results in organ ' 'fibrosis, the cause of which might be endothelial disorders arising during the ' 'endothelial-mesenchymal transition (EndMT).</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Methods</jats:title>\n' ' <jats:p>HUVECs and HMEC-1 cells were stimulated with SARS-CoV-2\xa0S (Spike) ' 'and N (Nucleocapsid) proteins, and EndMT induction was evaluated by studying specific protein ' 'markers via Western blotting. Wound healing and tube formation assays were employed to assess ' 'the potential of SARS-CoV-2 to stimulate changes in cell behaviour. MRTF nuclear ' 'translocation, ROS generation, TLR4 inhibitors, TGF-β-neutralizing antibodies, and inhibitors ' 'of the TGF-β-dependent pathway were used to investigate the role of the TGF-β-MRTF signalling ' 'axis in SARS-CoV-2-dependent EndMT stimulation.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Results</jats:title>\n' ' <jats:p>Both viral proteins stimulate myofibroblast trans-differentiation. ' 'However, the N protein is more effective at EndMT induction. The TGF-β-MRTF pathway plays a ' 'critical role in this process. The N protein preferentially favours action through TGF-β2, ' 'whose secretion is induced through TLR4-ROS action. TGF-β2 stimulates MRTF-A and MRTF-B ' 'nuclear translocation and strongly regulates EndMT. In contrast, the Spike protein stimulates ' 'TGF-β1 secretion as a result of ACE2 downregulation. TGF-β1 induces only MRTF-B, which, in ' 'turn, weakly regulates EndMT. Furthermore, aspirin, a common nonsteroidal anti-inflammatory ' 'drug, might prevent and reverse SARS-CoV-2-dependent EndMT induction through TGF-β-MRTF ' 'pathway deregulation.</jats:p>\n' ' </jats:sec><jats:sec>\n' ' <jats:title>Conclusion</jats:title>\n' ' <jats:p>The reported study revealed that SARS-CoV-2 infection induces EndMT. ' 'Moreover, it was demonstrated for the first time at the molecular level that the intensity of ' 'the EndMT triggered by SARS-CoV-2 infection may vary and depend on the viral protein ' 'involved. The N protein acts through TLR4-ROS-TGF-β2-MRTF-A/B, whereas the S protein acts ' 'through ACE2-TGF-β1-MRTF-B. Furthermore, we identified aspirin as a potential anti-fibrotic ' 'drug for treating patients with SARS-CoV-2 infection.</jats:p>\n' ' </jats:sec>', 'DOI': '10.1186/s12964-024-01665-z', 'type': 'journal-article', 'created': {'date-parts': [[2024, 5, 28]], 'date-time': '2024-05-28T15:08:55Z', 'timestamp': 1716908935000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Diverse roles of SARS-CoV-2 Spike and Nucleocapsid proteins in EndMT stimulation through the ' 'TGF-β-MRTF axis inhibited by aspirin', 'prefix': '10.1186', 'volume': '22', 'author': [ {'given': 'Wojciech M.', 'family': 'Ciszewski', 'sequence': 'first', 'affiliation': []}, {'given': 'Lucyna A.', 'family': 'Woźniak', 'sequence': 'additional', 'affiliation': []}, {'given': 'Katarzyna', 'family': 'Sobierajska', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2024, 5, 28]]}, 'reference': [ { 'key': '1665_CR1', 'doi-asserted-by': 'publisher', 'first-page': '119', 'DOI': '10.3345/cep.2020.00493', 'volume': '63', 'author': 'SE Park', 'year': '2020', 'unstructured': 'Park SE. Epidemiology, virology, and clinical features of severe acute ' 'respiratory syndrome -coronavirus-2 (SARS-CoV-2; coronavirus ' 'Disease-19). Clin Exp Pediatr. 2020;63:119–24.', 'journal-title': 'Clin Exp Pediatr'}, { 'key': '1665_CR2', 'unstructured': 'WorldHealthOrganization. Novel Coronavirus (2019-nCoV): situation ' 'report, 22. World Health Organization. 2022, ' 'https://iris.who.int/handle/10665/330991.'}, { 'key': '1665_CR3', 'doi-asserted-by': 'publisher', 'first-page': '740', 'DOI': '10.1016/j.ijbiomac.2021.08.076', 'volume': '188', 'author': 'H Fathizadeh', 'year': '2021', 'unstructured': 'Fathizadeh H, Afshar S, Masoudi MR, Gholizadeh P, Asgharzadeh M, ' 'Ganbarov K, Kose S, Yousefi M, Kafil HS. SARS-CoV-2 (Covid-19) vaccines ' 'structure, mechanisms and effectiveness: a review. Int J Biol Macromol. ' '2021;188:740–50.', 'journal-title': 'Int J Biol Macromol'}, { 'key': '1665_CR4', 'doi-asserted-by': 'publisher', 'first-page': '161', 'DOI': '10.1016/j.ijbiomac.2022.01.118', 'volume': '204', 'author': 'RM El-Shabasy', 'year': '2022', 'unstructured': 'El-Shabasy RM, Nayel MA, Taher MM, Abdelmonem R, Shoueir KR, Kenawy ER. ' 'Three waves changes, new variant strains, and vaccination effect against ' 'COVID-19 pandemic. Int J Biol Macromol. 2022;204:161–8.', 'journal-title': 'Int J Biol Macromol'}, { 'key': '1665_CR5', 'doi-asserted-by': 'publisher', 'first-page': '1122', 'DOI': '10.1126/science.abm8108', 'volume': '375', 'author': 'M Merad', 'year': '2022', 'unstructured': 'Merad M, Blish CA, Sallusto F, Iwasaki A. The immunology and ' 'immunopathology of COVID-19. Science. 2022;375:1122–7.', 'journal-title': 'Science'}, { 'key': '1665_CR6', 'doi-asserted-by': 'publisher', 'first-page': '92', 'DOI': '10.1186/s12985-022-01814-1', 'volume': '19', 'author': 'S Montazersaheb', 'year': '2022', 'unstructured': 'Montazersaheb S, Hosseiniyan Khatibi SM, Hejazi MS, Tarhriz V, Farjami ' 'A, Ghasemian Sorbeni F, Farahzadi R, Ghasemnejad T. COVID-19 infection: ' 'an overview on cytokine storm and related interventions. Virol J. ' '2022;19:92.', 'journal-title': 'Virol J'}, { 'key': '1665_CR7', 'doi-asserted-by': 'publisher', 'first-page': '823600', 'DOI': '10.3389/fmed.2021.823600', 'volume': '8', 'author': 'E Cocconcelli', 'year': '2021', 'unstructured': 'Cocconcelli E, Bernardinello N, Giraudo C, Castelli G, Giorgino A, Leoni ' 'D, Petrarulo S, Ferrari A, Saetta M, Cattelan A, et al. Characteristics ' 'and prognostic factors of Pulmonary Fibrosis after COVID-19 Pneumonia. ' 'Front Med (Lausanne). 2021;8:823600.', 'journal-title': 'Front Med (Lausanne)'}, { 'key': '1665_CR8', 'doi-asserted-by': 'crossref', 'unstructured': 'Poloni TE, Moretti M, Medici V, Turturici E, Belli G, Cavriani E, Visona ' 'SD, Rossi M, Fantini V, Ferrari RR et al. COVID-19 Pathology in the ' 'Lung, Kidney, Heart and Brain: The Different Roles of T-Cells, ' 'Macrophages, and Microthrombosis. Cells 2022, 11.', 'DOI': '10.3390/cells11193124'}, { 'key': '1665_CR9', 'doi-asserted-by': 'publisher', 'first-page': '755', 'DOI': '10.1007/s10456-021-09805-6', 'volume': '24', 'author': 'DM Smadja', 'year': '2021', 'unstructured': 'Smadja DM, Mentzer SJ, Fontenay M, Laffan MA, Ackermann M, Helms J, ' 'Jonigk D, Chocron R, Pier GB, Gendron N, et al. COVID-19 is a systemic ' 'vascular hemopathy: insight for mechanistic and clinical aspects. ' 'Angiogenesis. 2021;24:755–88.', 'journal-title': 'Angiogenesis'}, { 'key': '1665_CR10', 'doi-asserted-by': 'publisher', 'first-page': '14361', 'DOI': '10.1038/ncomms14361', 'volume': '8', 'author': 'E Dejana', 'year': '2017', 'unstructured': 'Dejana E, Hirschi KK, Simons M. The molecular basis of endothelial cell ' 'plasticity. Nat Commun. 2017;8:14361.', 'journal-title': 'Nat Commun'}, { 'key': '1665_CR11', 'doi-asserted-by': 'publisher', 'first-page': '1281', 'DOI': '10.1152/physrev.00021.2018', 'volume': '99', 'author': 'S Piera-Velazquez', 'year': '2019', 'unstructured': 'Piera-Velazquez S, Jimenez SA. Endothelial to mesenchymal transition: ' 'role in physiology and in the Pathogenesis of Human diseases. Physiol ' 'Rev. 2019;99:1281–324.', 'journal-title': 'Physiol Rev'}, { 'key': '1665_CR12', 'doi-asserted-by': 'publisher', 'first-page': '101530', 'DOI': '10.1016/j.jbc.2021.101530', 'volume': '298', 'author': 'L Moretti', 'year': '2022', 'unstructured': 'Moretti L, Stalfort J, Barker TH, Abebayehu D. The interplay of ' 'fibroblasts, the extracellular matrix, and inflammation in scar ' 'formation. J Biol Chem. 2022;298:101530.', 'journal-title': 'J Biol Chem'}, { 'key': '1665_CR13', 'doi-asserted-by': 'publisher', 'first-page': '747', 'DOI': '10.3389/fcell.2020.00747', 'volume': '8', 'author': 'N Clere', 'year': '2020', 'unstructured': 'Clere N, Renault S, Corre I. Endothelial-to-mesenchymal transition in ' 'Cancer. Front Cell Dev Biol. 2020;8:747.', 'journal-title': 'Front Cell Dev Biol'}, { 'key': '1665_CR14', 'doi-asserted-by': 'crossref', 'unstructured': 'Eapen MS, Lu W, Gaikwad AV, Bhattarai P, Chia C, Hardikar A, Haug G, ' 'Sohal SS. Endothelial to mesenchymal transition: a precursor to ' 'post-COVID-19 interstitial pulmonary fibrosis and vascular obliteration? ' 'Eur Respir J 2020, 56.', 'DOI': '10.1183/13993003.03167-2020'}, { 'key': '1665_CR15', 'doi-asserted-by': 'publisher', 'first-page': '415', 'DOI': '10.1007/s00418-022-02140-x', 'volume': '158', 'author': 'P Gal', 'year': '2022', 'unstructured': 'Gal P, Brabek J, Holub M, Jakubek M, Sedo A, Lacina L, Strnadova K, ' 'Dubovy P, Hornychova H, Ryska A, Smetana K Jr. Autoimmunity, cancer and ' 'COVID-19 abnormally activate wound healing pathways: critical role of ' 'inflammation. Histochem Cell Biol. 2022;158:415–34.', 'journal-title': 'Histochem Cell Biol'}, { 'key': '1665_CR16', 'doi-asserted-by': 'publisher', 'first-page': '976512', 'DOI': '10.3389/fimmu.2022.976512', 'volume': '13', 'author': 'L Zhang', 'year': '2022', 'unstructured': 'Zhang L, Tang C, Zhang M, Tong X, Xie Y, Yan R, Wang X, Zhang X, Liu D, ' 'Li S. Single cell meta-analysis of EndMT and EMT state in COVID-19. ' 'Front Immunol. 2022;13:976512.', 'journal-title': 'Front Immunol'}, { 'key': '1665_CR17', 'doi-asserted-by': 'publisher', 'first-page': '905', 'DOI': '10.1007/s10096-020-04138-6', 'volume': '40', 'author': 'S Beyerstedt', 'year': '2021', 'unstructured': 'Beyerstedt S, Casaro EB, Rangel EB. COVID-19: angiotensin-converting ' 'enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 ' 'infection. Eur J Clin Microbiol Infect Dis. 2021;40:905–19.', 'journal-title': 'Eur J Clin Microbiol Infect Dis'}, { 'key': '1665_CR18', 'doi-asserted-by': 'publisher', 'first-page': '3', 'DOI': '10.1038/s41580-021-00418-x', 'volume': '23', 'author': 'CB Jackson', 'year': '2022', 'unstructured': 'Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry ' 'into cells. Nat Rev Mol Cell Biol. 2022;23:3–20.', 'journal-title': 'Nat Rev Mol Cell Biol'}, { 'key': '1665_CR19', 'doi-asserted-by': 'crossref', 'unstructured': 'Pardali E, Sanchez-Duffhues G, Gomez-Puerto MC, Ten Dijke P. ' 'TGF-beta-Induced endothelial-mesenchymal transition in Fibrotic ' 'diseases. Int J Mol Sci 2017, 18.', 'DOI': '10.3390/ijms18102157'}, { 'key': '1665_CR20', 'doi-asserted-by': 'publisher', 'first-page': '260', 'DOI': '10.3389/fcell.2020.00260', 'volume': '8', 'author': 'J Ma', 'year': '2020', 'unstructured': 'Ma J, Sanchez-Duffhues G, Goumans MJ, Ten Dijke P. TGF-beta-Induced ' 'endothelial to mesenchymal transition in Disease and tissue Engineering. ' 'Front Cell Dev Biol. 2020;8:260.', 'journal-title': 'Front Cell Dev Biol'}, { 'key': '1665_CR21', 'doi-asserted-by': 'publisher', 'first-page': 'e12327', 'DOI': '10.1016/j.heliyon.2022.e12327', 'volume': '8', 'author': 'P Yadav', 'year': '2022', 'unstructured': 'Yadav P, Chowdhury P. Effectivity of repurposed drugs against SARS-CoV-2 ' 'infections, a hope for COVID 19: inhibitor modelling studies by docking ' 'and molecular dynamics. Heliyon. 2022;8:e12327.', 'journal-title': 'Heliyon'}, { 'key': '1665_CR22', 'doi-asserted-by': 'publisher', 'first-page': '103385', 'DOI': '10.1016/j.arabjc.2021.103385', 'volume': '14', 'author': 'AS Ali', 'year': '2021', 'unstructured': 'Ali AS, Ibrahim IM, Burzangi AS, Ghoneim RH, Aljohani HS, Alsamhan HA, ' 'Barakat J. Scoping insight on antiviral drugs against COVID-19. Arab J ' 'Chem. 2021;14:103385.', 'journal-title': 'Arab J Chem'}, { 'key': '1665_CR23', 'doi-asserted-by': 'publisher', 'first-page': '2531', 'DOI': '10.1016/j.ajpath.2019.08.004', 'volume': '189', 'author': 'K Sobierajska', 'year': '2019', 'unstructured': 'Sobierajska K, Wawro ME, Ciszewski WM, Niewiarowska J. Transforming ' 'growth factor-beta receptor internalization via Caveolae is regulated by ' 'Tubulin-beta2 and Tubulin-beta3 during endothelial-mesenchymal ' 'transition. Am J Pathol. 2019;189:2531–46.', 'journal-title': 'Am J Pathol'}, { 'key': '1665_CR24', 'doi-asserted-by': 'crossref', 'unstructured': 'Sobierajska K, Ciszewski WM, Macierzynska-Piotrowska E, Klopocka W, ' 'Przygodzka P, Karakula M, Pestka K, Wawro ME, Niewiarowska J. The New ' 'Model of snail expression regulation: the role of MRTFs in fast and slow ' 'endothelial-mesenchymal transition. Int J Mol Sci 2020, 21.', 'DOI': '10.3390/ijms21165875'}, { 'key': '1665_CR25', 'doi-asserted-by': 'crossref', 'unstructured': 'Ciszewski WM, Chmielewska-Kassassir M, Wozniak LA, Sobierajska K. ' 'Thymidylate synthase overexpression drives the invasive phenotype in ' 'Colon cancer cells. Biomedicines 2022, 10.', 'DOI': '10.3390/biomedicines10061267'}, { 'key': '1665_CR26', 'doi-asserted-by': 'crossref', 'unstructured': 'Aboudounya MM, Heads RJ. COVID-19 and Toll-Like Receptor 4 (TLR4): ' 'SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, ' 'Facilitating Entry and Causing Hyperinflammation. Mediators Inflamm ' '2021, 2021:8874339.', 'DOI': '10.1155/2021/8874339'}, { 'key': '1665_CR27', 'doi-asserted-by': 'publisher', 'first-page': '14', 'DOI': '10.1016/j.fct.2014.01.018', 'volume': '66', 'author': 'Q Yu', 'year': '2014', 'unstructured': 'Yu Q, Nie SP, Wang JQ, Yin PF, Huang DF, Li WJ, Xie MY. Toll-like ' 'receptor 4-mediated ROS signaling pathway involved in Ganoderma Atrum ' 'polysaccharide-induced tumor necrosis factor-alpha secretion during ' 'macrophage activation. Food Chem Toxicol. 2014;66:14–22.', 'journal-title': 'Food Chem Toxicol'}, { 'key': '1665_CR28', 'doi-asserted-by': 'crossref', 'unstructured': 'Ciszewski WM, Wawro ME, Sacewicz-Hofman I, Sobierajska K. Cytoskeleton ' 'reorganization in EndMT-The role in Cancer and Fibrotic diseases. Int J ' 'Mol Sci 2021, 22.', 'DOI': '10.3390/ijms222111607'}, { 'key': '1665_CR29', 'doi-asserted-by': 'crossref', 'unstructured': 'Wawro ME, Sobierajska K, Ciszewski WM, Niewiarowska J. Nonsteroidal ' 'anti-inflammatory drugs prevent Vincristine-Dependent Cancer-Associated ' 'fibroblasts formation. Int J Mol Sci 2019, 20.', 'DOI': '10.3390/ijms20081941'}, { 'key': '1665_CR30', 'doi-asserted-by': 'publisher', 'first-page': '2132', 'DOI': '10.3389/fimmu.2020.02132', 'volume': '11', 'author': 'V Castelli', 'year': '2020', 'unstructured': 'Castelli V, Cimini A, Ferri C. Cytokine storm in COVID-19: when you come ' 'out of the storm, you won’t be the same person who walked in. Front ' 'Immunol. 2020;11:2132.', 'journal-title': 'Front Immunol'}, { 'key': '1665_CR31', 'doi-asserted-by': 'publisher', 'first-page': '807', 'DOI': '10.1016/S2213-2600(20)30225-3', 'volume': '8', 'author': 'PM George', 'year': '2020', 'unstructured': 'George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the ' 'potential role for antifibrotic therapy. Lancet Respir Med. ' '2020;8:807–15.', 'journal-title': 'Lancet Respir Med'}, { 'key': '1665_CR32', 'doi-asserted-by': 'publisher', 'first-page': '217', 'DOI': '10.1016/j.stem.2021.12.010', 'volume': '29', 'author': 'J Jansen', 'year': '2022', 'unstructured': 'Jansen J, Reimer KC, Nagai JS, Varghese FS, Overheul GJ, de Beer M, ' 'Roverts R, Daviran D, Fermin LAS, Willemsen B, et al. SARS-CoV-2 infects ' 'the human kidney and drives fibrosis in kidney organoids. Cell Stem ' 'Cell. 2022;29:217–e231218.', 'journal-title': 'Cell Stem Cell'}, { 'key': '1665_CR33', 'doi-asserted-by': 'publisher', 'first-page': '740260', 'DOI': '10.3389/fimmu.2021.740260', 'volume': '12', 'author': 'J Mustroph', 'year': '2021', 'unstructured': 'Mustroph J, Hupf J, Baier MJ, Evert K, Brochhausen C, Broeker K, Meindl ' 'C, Seither B, Jungbauer C, Evert M, et al. Cardiac Fibrosis is a risk ' 'factor for severe COVID-19. Front Immunol. 2021;12:740260.', 'journal-title': 'Front Immunol'}, { 'key': '1665_CR34', 'doi-asserted-by': 'publisher', 'first-page': '370', 'DOI': '10.1186/s12876-021-01939-7', 'volume': '21', 'author': 'O Kolesova', 'year': '2021', 'unstructured': 'Kolesova O, Vanaga I, Laivacuma S, Derovs A, Kolesovs A, Radzina M, ' 'Platkajis A, Eglite J, Hagina E, Arutjunana S, et al. Intriguing ' 'findings of liver fibrosis following COVID-19. BMC Gastroenterol. ' '2021;21:370.', 'journal-title': 'BMC Gastroenterol'}, { 'key': '1665_CR35', 'doi-asserted-by': 'publisher', 'first-page': '555', 'DOI': '10.1038/s41586-020-2938-9', 'volume': '587', 'author': 'NC Henderson', 'year': '2020', 'unstructured': 'Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. ' 'Nature. 2020;587:555–66.', 'journal-title': 'Nature'}, { 'key': '1665_CR36', 'doi-asserted-by': 'publisher', 'first-page': '271', 'DOI': '10.1016/j.cell.2020.02.052', 'volume': '181', 'author': 'M Hoffmann', 'year': '2020', 'unstructured': 'Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen ' 'S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al. SARS-CoV-2 cell ' 'entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven ' 'protease inhibitor. Cell. 2020;181:271–e280278.', 'journal-title': 'Cell'}, { 'key': '1665_CR37', 'doi-asserted-by': 'publisher', 'first-page': '1141', 'DOI': '10.1038/s41401-020-0485-4', 'volume': '41', 'author': 'Y Huang', 'year': '2020', 'unstructured': 'Huang Y, Yang C, Xu XF, Xu W, Liu SW. Structural and functional ' 'properties of SARS-CoV-2 spike protein: potential antivirus drug ' 'development for COVID-19. Acta Pharmacol Sin. 2020;41:1141–9.', 'journal-title': 'Acta Pharmacol Sin'}, { 'key': '1665_CR38', 'doi-asserted-by': 'publisher', 'first-page': '6', 'DOI': '10.1186/s12985-023-01968-6', 'volume': '20', 'author': 'W Wu', 'year': '2023', 'unstructured': 'Wu W, Cheng Y, Zhou H, Sun C, Zhang S. The SARS-CoV-2 nucleocapsid ' 'protein: its role in the viral life cycle, structure and functions, and ' 'use as a potential target in the development of vaccines and ' 'diagnostics. Virol J. 2023;20:6.', 'journal-title': 'Virol J'}, { 'key': '1665_CR39', 'doi-asserted-by': 'crossref', 'unstructured': 'Khan S, Shafiei MS, Longoria C, Schoggins JW, Savani RC, Zaki H. ' 'SARS-CoV-2 spike protein induces inflammation via TLR2-dependent ' 'activation of the NF-kappaB pathway. Elife 2021, 10.', 'DOI': '10.7554/eLife.68563'}, { 'key': '1665_CR40', 'doi-asserted-by': 'publisher', 'first-page': '431', 'DOI': '10.1042/CS20220028', 'volume': '136', 'author': 'JD Imig', 'year': '2022', 'unstructured': 'Imig JD. SARS-CoV-2 spike protein causes cardiovascular disease ' 'independent of viral infection. Clin Sci (Lond). 2022;136:431–4.', 'journal-title': 'Clin Sci (Lond)'}, { 'key': '1665_CR41', 'doi-asserted-by': 'publisher', 'first-page': '240', 'DOI': '10.1093/clinchem/hvab148', 'volume': '68', 'author': 'Y Zhang', 'year': '2021', 'unstructured': 'Zhang Y, Ong CM, Yun C, Mo W, Whitman JD, Lynch KL, Wu AHB. Diagnostic ' 'Value of Nucleocapsid Protein in blood for SARS-CoV-2 infection. Clin ' 'Chem. 2021;68:240–8.', 'journal-title': 'Clin Chem'}, { 'key': '1665_CR42', 'doi-asserted-by': 'publisher', 'first-page': '791', 'DOI': '10.1038/s41467-023-36333-2', 'volume': '14', 'author': 'R Mothes', 'year': '2023', 'unstructured': 'Mothes R, Pascual-Reguant A, Koehler R, Liebeskind J, Liebheit A, ' 'Bauherr S, Philipsen L, Dittmayer C, Laue M, von Manitius R, et al. ' 'Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 ' 'in severe COVID-19. Nat Commun. 2023;14:791.', 'journal-title': 'Nat Commun'}, { 'key': '1665_CR43', 'doi-asserted-by': 'publisher', 'first-page': '120', 'DOI': '10.1056/NEJMoa2015432', 'volume': '383', 'author': 'M Ackermann', 'year': '2020', 'unstructured': 'Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, ' 'Vanstapel A, Werlein C, Stark H, Tzankov A, et al. Pulmonary vascular ' 'endothelialitis, thrombosis, and Angiogenesis in Covid-19. N Engl J Med. ' '2020;383:120–8.', 'journal-title': 'N Engl J Med'}, { 'key': '1665_CR44', 'doi-asserted-by': 'publisher', 'first-page': '1417', 'DOI': '10.1016/S0140-6736(20)30937-5', 'volume': '395', 'author': 'Z Varga', 'year': '2020', 'unstructured': 'Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel ' 'AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H. Endothelial cell ' 'infection and endotheliitis in COVID-19. Lancet. 2020;395:1417–8.', 'journal-title': 'Lancet'}, { 'key': '1665_CR45', 'doi-asserted-by': 'crossref', 'unstructured': 'Bai Z, Cao Y, Liu W, Li J. The SARS-CoV-2 nucleocapsid protein and its ' 'role in viral structure, Biological functions, and a potential target ' 'for drug or vaccine mitigation. 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