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

Zhouyi Rong; Hongcheng Mai; Gregor Ebert; Saketh Kapoor; Victor G. Puelles; Jan Czogalla; Senbin Hu; Jinpeng Su; Danilo Prtvar; Inderjeet Singh; Julia Schädler; Claire Delbridge; Hanno Steinke; Hannah Frenzel; Katja Schmidt; Christian Braun; Gina Bruch; Viktoria Ruf; Mayar Ali; Kurt Wolfram Sühs; Mojtaba Nemati; Franziska Hopfner; Selin Ulukaya; Denise Jeridi; Daniele Mistretta; Özüm Sehnaz Caliskan; Jochen Martin Wettengel; Fatma Cherif; Zeynep Ilgin Kolabas; Müge Molbay; Izabela Horvath; Shan Zhao; Natalie Krahmer; Ali Önder Yildirim; Siegfried Ussar; Jochen Herms; Tobias B. Huber; Sabina Tahirovic; Susanne M. Schwarzmaier; Nikolaus Plesnila; Günter Höglinger; Benjamin Ondruschka; Ingo Bechmann; Ulrike Protzer; Markus Elsner; Harsharan Singh Bhatia; Farida Hellal; Ali Ertürk

doi:10.1016/j.chom.2024.11.007

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

Zhouyi Rong, Hongcheng Mai, Gregor Ebert, Saketh Kapoor, Victor G. Puelles, Jan Czogalla, Senbin Hu, Jinpeng Su, Danilo Prtvar, Inderjeet Singh, Julia Schädler, Claire Delbridge, Hanno Steinke, Hannah Frenzel, Katja Schmidt, Christian Braun, Gina Bruch, Viktoria Ruf, Mayar Ali, Kurt Wolfram SühsMojtaba Nemati, Franziska Hopfner, Selin Ulukaya, Denise Jeridi, Daniele Mistretta, Özüm Sehnaz Caliskan, Jochen Martin Wettengel, Fatma Cherif, Zeynep Ilgin Kolabas, Müge Molbay, Izabela Horvath, Shan Zhao, Natalie Krahmer, Ali Önder Yildirim, Siegfried Ussar, Jochen Herms, Tobias B. Huber, Sabina Tahirovic, Susanne M. Schwarzmaier, Nikolaus Plesnila, Günter Höglinger, Benjamin Ondruschka, Ingo Bechmann, Ulrike Protzer, Markus Elsner, Harsharan Singh Bhatia, Farida Hellal, Ali Ertürk^*

^*Corresponding author for this work

Department of Clinical Medicine - The Department of Pathology

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

13 Citations (Scopus)

Abstract

SARS-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.

Original language	English
Journal	Cell Host and Microbe
Volume	32
Issue	12
Pages (from-to)	2112-2130.e10
ISSN	1931-3128
DOIs	https://doi.org/10.1016/j.chom.2024.11.007
Publication status	Published - 11 Dec 2024

Keywords

brain
long COVID
meninges
mRNA vaccine
neurodegeneration
neuroinflammation
SARS-CoV-2
skull
spike protein
tissue clearing

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Rong, 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., ... Ertürk, A. (2024). Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19. Cell Host and Microbe, 32(12), 2112-2130.e10. https://doi.org/10.1016/j.chom.2024.11.007

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title = "Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19",

abstract = "SARS-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.",

keywords = "brain, long COVID, meninges, mRNA vaccine, neurodegeneration, neuroinflammation, SARS-CoV-2, skull, spike protein, tissue clearing",

author = "Zhouyi Rong and Hongcheng Mai and Gregor Ebert and Saketh Kapoor and Puelles, {Victor G.} and Jan Czogalla and Senbin Hu and Jinpeng Su and Danilo Prtvar and Inderjeet Singh and Julia Sch{\"a}dler and Claire Delbridge and Hanno Steinke and Hannah Frenzel and Katja Schmidt and Christian Braun and Gina Bruch and Viktoria Ruf and Mayar Ali and S{\"u}hs, {Kurt Wolfram} and Mojtaba Nemati and Franziska Hopfner and Selin Ulukaya and Denise Jeridi and Daniele Mistretta and Caliskan, {{\"O}z{\"u}m Sehnaz} and Wettengel, {Jochen Martin} and Fatma Cherif and Kolabas, {Zeynep Ilgin} and M{\"u}ge Molbay and Izabela Horvath and Shan Zhao and Natalie Krahmer and Yildirim, {Ali {\"O}nder} and Siegfried Ussar and Jochen Herms and Huber, {Tobias B.} and Sabina Tahirovic and Schwarzmaier, {Susanne M.} and Nikolaus Plesnila and G{\"u}nter H{\"o}glinger and Benjamin Ondruschka and Ingo Bechmann and Ulrike Protzer and Markus Elsner and Bhatia, {Harsharan Singh} and Farida Hellal and Ali Ert{\"u}rk",

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year = "2024",

month = dec,

day = "11",

doi = "10.1016/j.chom.2024.11.007",

language = "English",

volume = "32",

pages = "2112--2130.e10",

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Rong, Z, Mai, H, Ebert, G, Kapoor, S, Puelles, VG, 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, KW, Nemati, M, Hopfner, F, Ulukaya, S, Jeridi, D, Mistretta, D, Caliskan, ÖS, Wettengel, JM, Cherif, F, Kolabas, ZI, Molbay, M, Horvath, I, Zhao, S, Krahmer, N, Yildirim, AÖ, Ussar, S, Herms, J, Huber, TB, Tahirovic, S, Schwarzmaier, SM, Plesnila, N, Höglinger, G, Ondruschka, B, Bechmann, I, Protzer, U, Elsner, M, Bhatia, HS, Hellal, F & Ertürk, A 2024, 'Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19', Cell Host and Microbe, vol. 32, no. 12, pp. 2112-2130.e10. https://doi.org/10.1016/j.chom.2024.11.007

Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19. / Rong, Zhouyi; Mai, Hongcheng; Ebert, Gregor et al.
In: Cell Host and Microbe, Vol. 32, No. 12, 11.12.2024, p. 2112-2130.e10.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19

AU - Rong, Zhouyi

AU - Mai, Hongcheng

AU - Ebert, Gregor

AU - Kapoor, Saketh

AU - Puelles, Victor G.

AU - Czogalla, Jan

AU - Hu, Senbin

AU - Su, Jinpeng

AU - Prtvar, Danilo

AU - Singh, Inderjeet

AU - Schädler, Julia

AU - Delbridge, Claire

AU - Steinke, Hanno

AU - Frenzel, Hannah

AU - Schmidt, Katja

AU - Braun, Christian

AU - Bruch, Gina

AU - Ruf, Viktoria

AU - Ali, Mayar

AU - Sühs, Kurt Wolfram

AU - Nemati, Mojtaba

AU - Hopfner, Franziska

AU - Ulukaya, Selin

AU - Jeridi, Denise

AU - Mistretta, Daniele

AU - Caliskan, Özüm Sehnaz

AU - Wettengel, Jochen Martin

AU - Cherif, Fatma

AU - Kolabas, Zeynep Ilgin

AU - Molbay, Müge

AU - Horvath, Izabela

AU - Zhao, Shan

AU - Krahmer, Natalie

AU - Yildirim, Ali Önder

AU - Ussar, Siegfried

AU - Herms, Jochen

AU - Huber, Tobias B.

AU - Tahirovic, Sabina

AU - Schwarzmaier, Susanne M.

AU - Plesnila, Nikolaus

AU - Höglinger, Günter

AU - Ondruschka, Benjamin

AU - Bechmann, Ingo

AU - Protzer, Ulrike

AU - Elsner, Markus

AU - Bhatia, Harsharan Singh

AU - Hellal, Farida

AU - Ertürk, Ali

PY - 2024/12/11

Y1 - 2024/12/11

N2 - SARS-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.

AB - SARS-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.

KW - brain

KW - long COVID

KW - meninges

KW - mRNA vaccine

KW - neurodegeneration

KW - neuroinflammation

KW - SARS-CoV-2

KW - skull

KW - spike protein

KW - tissue clearing

UR - http://www.scopus.com/inward/record.url?scp=85211122637&partnerID=8YFLogxK

U2 - 10.1016/j.chom.2024.11.007

DO - 10.1016/j.chom.2024.11.007

M3 - Journal article

C2 - 39615487

AN - SCOPUS:85211122637

SN - 1931-3128

VL - 32

SP - 2112-2130.e10

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 12

ER -

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

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Keywords

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