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Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of Covid-19

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dc.contributor.coauthorRong Z., Mai H., Ebert G., Kapoor S., Puelles V.G., Czogalla J., Hu S., Su J., Prtvar D., Singh I., Schädler J., Delbridge C., Steinke H., Frenzel H., Schmidt K., Braun C., Bruch G., Ruf V., Ali M., Sühs K.-W., Nemati M., Hopfner F., Ulukaya S., Jeridi D., Mistretta D., Caliskan Ö.S., Wettengel J.M., Cherif F., Kolabas Z.I., Molbay M., Horvath I., Zhao S., Krahmer N., Yildirim A.Ö., Ussar S., Herms J., Huber T.B., Tahirovic S., Schwarzmaier S.M., Plesnila N., Höglinger G., Ondruschka B., Bechmann I., Protzer U., Elsner M., Bhatia H.S., Hellal F.
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorErtürk, Ali Maximilian
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2025-03-06T20:57:44Z
dc.date.issued2024
dc.description.abstractSARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear. Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance. Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes. Similar distribution patterns of the spike protein were observed in SARS-CoV-2-infected mice. Injection of spike protein alone was sufficient to induce neuroinflammation, proteome changes in the skull-meninges-brain axis, anxiety-like behavior, and exacerbated outcomes in mouse models of stroke and traumatic brain injury. Vaccination reduced but did not eliminate spike protein accumulation after infection in mice. Our findings suggest persistent spike protein at the brain borders may contribute to lasting neurological sequelae of COVID-19. © 2024 The Author(s)
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipWe thank Alireza Ghasemi for developing the Python script to stitch sequences of images. We thank Christoph Krisp (Bruker Daltonics) for helpful discussions on mass spectrometer data acquisition. We thank Mrs. Brigitte Nuscher for her assistance with the Simoa assay. Illustrations were created with BioRender.com. Z.R. and H.M. thank the China Scholarship Council (CSC) for the financial support (no. 201806310110 and no. 201806780034). We acknowledge all families supporting our research after losing their beloved ones during the pandemic. This work was supported by the European Research Council Consolidator grant (CALVARIA, grant no. GA 865323 to A.E.), the NOMIS Human Heart Atlas Project grant (Nomis Foundation), the Vascular Dementia Research Foundation, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198), and the German Federal Ministry of Education and Research (Bundesministerium f\u00FCr Bildung und Forschung, BMBF) within the NATON collaboration (01KX2121) and DFG (SFB 1052, project A9;TR 296 project 03;TRR353/B02 to G.E.). This work was also supported by the State of Bavaria and the European Union via a grant for regional infrastructure development (EFRE-REACT to U.P. and G.E.) by the Helmholtz Association's Initiative and Networking Fund (KA1-Co-06, \u201CCORAERO\u201D to G.E.) and a GoBio project (16LW0286K to G.E. and U.P.). G.H., K.-W.S., M.N., and F. Hopfner are supported through the COFONI-2FF4/COVID-19-Research Network of the State of Lower Saxony (COFONI), Ministry of Science and Culture of Lower Saxony, Germany.
dc.identifier.doi10.1016/j.chom.2024.11.007
dc.identifier.eissn1934-6069
dc.identifier.grantnoNiedersächsische Ministerium für Wissenschaft und Kultur; European Commission, EC; Stiftung zur Erforschung der Vaskulären Demenz; NOMIS Stiftung; Bundesministerium für Bildung und Forschung, BMBF: SFB 1052, TR 296, TRR353/B02, 01KX2121; Bundesministerium für Bildung und Forschung, BMBF; Deutsche Forschungsgemeinschaft, DFG: 390857198; Deutsche Forschungsgemeinschaft, DFG; China Scholarship Council, CSC: 201806310110, 201806780034; China Scholarship Council, CSC; European Research Council, ERC: GA 865323; European Research Council, ERC; Helmholtz Association: KA1-Co-06, 16LW0286K; Helmholtz Association
dc.identifier.issn1931-3128
dc.identifier.issue12
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85211122637
dc.identifier.urihttps://doi.org/10.1016/j.chom.2024.11.007
dc.identifier.urihttps://hdl.handle.net/20.500.14288/27295
dc.identifier.volume32
dc.identifier.wos1388863700001
dc.keywordsBrain
dc.keywordsLong covid
dc.keywordsMeninges
dc.keywordsMrna vaccine
dc.keywordsNeurodegeneration
dc.keywordsNeuroinflammation
dc.keywordsSars-cov-2
dc.keywordsSkull
dc.keywordsSpike protein
dc.keywordsTissue clearing
dc.language.isoeng
dc.publisherCell Press
dc.relation.ispartofCell Host and Microbe
dc.subjectMedicine
dc.titlePersistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of Covid-19
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorErtürk, Ali Maximilian
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit2School of Medicine
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relation.isParentOrgUnitOfPublication17f2dc8e-6e54-4fa8-b5e0-d6415123a93e
relation.isParentOrgUnitOfPublication.latestForDiscovery17f2dc8e-6e54-4fa8-b5e0-d6415123a93e

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