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Deep Spatial Profiling of COVID-19 Brains Reveals Neuroinflammation by Compartmentalized Local Immune Cell Interactions and Targets for Intervention

50 Pages Posted: 13 Jan 2021 Publication Status: Review Complete

See all articles by Marius Schwabenland

Marius Schwabenland

University of Freiburg - Institute of Neuropathology

Henrike Salié

University Medical Center Freiburg - Clinic for Internal Medicine II

Jovan Tanevski

Heidelberg University and Heidelberg University Hospital - Institute for Computational Biomedicine

Saskia Killmer

University Medical Center Freiburg - Clinic for Internal Medicine II

Marilyn Salvat Lago

University Medical Center Freiburg - Clinic for Internal Medicine II

Jakob Matschke

University Medical Center Hamburg-Eppendorf - Institute of Neuropathology

Klaus Pueschel

University Medical Center Hamburg-Eppendorf - Institute of Legal Medicine

Henrik E. Mei

German Rheumatism Research Center (DRFZ)

Tobias Boettler

University Medical Center Freiburg - Clinic for Internal Medicine II

Christoph Neumann-Haefelin

University Medical Center Freiburg - Clinic for Internal Medicine II

Maike Hofmann

University Medical Center Freiburg - Clinic for Internal Medicine II

Angele Breithaupt

Friedrich-Loeffler-Institut - Department of Experimental Animal Facilities and Biorisk Management

Christine Stadelmann-Nesser

University of Goettingen - Instute of Neuropathology

Julio Saez-Rodriguez

Heidelberg University and Heidelberg University Hospital - Institute for Computational Biomedicine

Klaus-Peter Knobeloch

University of Freiburg - Center for Basics in NeuroModulation (NeuroModulBasics); University of Freiburg - Institute of Neuropathology

Thomas Blank

University of Freiburg - Institute of Neuropathology

Robert Thimme

University Medical Center Freiburg - Clinic for Internal Medicine II

Markus Glatzel

University Medical Center Hamburg-Eppendorf - Institute of Neuropathology

Marco Prinz

University of Freiburg - Institute of Neuropathology

Bertram Bengsch

University Medical Center Freiburg - Clinic for Internal Medicine II

More...

Abstract

COVID-19 can cause acute and chronic neurological symptoms. The underlying pathophysiological mechanisms, the involved immune cells, their spatial distribution, cellular interactions and the role of virus tropism remain largely unclear. Here, we deeply interrogated the brain stem and olfactory bulb in COVID-19 patients with imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional single-cell level. We observed significant immune activation in the CNS and identified distinct phenotypes of T cells and microglial clusters, their presence in specific anatomical regions and context-specific cellular interactions. Microglial nodules and perivascular immune cell clusters constitute key sites of the local immune response, with viral antigen present in ACE2-expressing cells in the perivascular compartment. Disease-associated neuroinflammation is associated with astrogliosis and severe axonal damage as a structural basis for the neurologic deficits. Finally, we identify compartment- and cluster-specific immune checkpoints that can be targeted for future therapeutic interventions.

Funding: This project was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, GermanResearch Foundation) (SFB 992, SFB1160, SFB/TRR167, SFB/TRR179, German Excellency strategyCIBSS - EXC-2189– Project ID390939984) and special research funds from the Ministry for Science, Research and Art of Baden-Wuerttemberg dedicated to “COVID-19 research” and “Neuroinflammation”.B.B. was further supported by DFG grant BE-5496/5-1 and M.P. was further supported by the Sobek Foundation, the Ernst-Jung Foundation, the Reinhart-Koselleck-Grant and Gottfried Wilhelm Leibniz-Prize.H.E.M. was supported by DFG ME-3644/5-1.

Ethical Approval: The analyses were performed with the approval of the Institutional Review Boards (Ethic Committee of the Albert-Ludwigs-University, Freiburg: 322/20, 10008/09; Ethics Committee of the Hamburg Chamber of Physicians: WF-051/20, PV7311). The study was performed in agreement with the principles expressed in the Declaration of Helsinki (2013).

Conflict of Interest: None to declare.

Suggested Citation

Schwabenland, Marius and Salié, Henrike and Tanevski, Jovan and Killmer, Saskia and Salvat Lago, Marilyn and Matschke, Jakob and Pueschel, Klaus and Mei, Henrik E. and Boettler, Tobias and Neumann-Haefelin, Christoph and Hofmann, Maike and Breithaupt, Angele and Stadelmann-Nesser, Christine and Saez-Rodriguez, Julio and Knobeloch, Klaus-Peter and Blank, Thomas and Thimme, Robert and Glatzel, Markus and Prinz, Marco and Bengsch, Bertram, Deep Spatial Profiling of COVID-19 Brains Reveals Neuroinflammation by Compartmentalized Local Immune Cell Interactions and Targets for Intervention. Available at SSRN: https://ssrn.com/abstract=3765620 or http://dx.doi.org/10.2139/ssrn.3765620
This version of the paper has not been formally peer reviewed.

Marius Schwabenland

University of Freiburg - Institute of Neuropathology ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Henrike Salié

University Medical Center Freiburg - Clinic for Internal Medicine II ( email )

Germany

Jovan Tanevski

Heidelberg University and Heidelberg University Hospital - Institute for Computational Biomedicine ( email )

Grabengasse 1
Heidelberg, 69117
Germany

Saskia Killmer

University Medical Center Freiburg - Clinic for Internal Medicine II ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Marilyn Salvat Lago

University Medical Center Freiburg - Clinic for Internal Medicine II ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Jakob Matschke

University Medical Center Hamburg-Eppendorf - Institute of Neuropathology ( email )

Hamburg
Germany

Klaus Pueschel

University Medical Center Hamburg-Eppendorf - Institute of Legal Medicine ( email )

Martinistrasse 52
Hamburg, D - 20246
Germany

Henrik E. Mei

German Rheumatism Research Center (DRFZ) ( email )

Berlin, 10117
Germany

Tobias Boettler

University Medical Center Freiburg - Clinic for Internal Medicine II ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Christoph Neumann-Haefelin

University Medical Center Freiburg - Clinic for Internal Medicine II ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Maike Hofmann

University Medical Center Freiburg - Clinic for Internal Medicine II ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Angele Breithaupt

Friedrich-Loeffler-Institut - Department of Experimental Animal Facilities and Biorisk Management

Greifswald-Insel Riems
Germany

Christine Stadelmann-Nesser

University of Goettingen - Instute of Neuropathology ( email )

Platz der Gottinger Sieben 3
Gottingen, D-37073
Germany

Julio Saez-Rodriguez

Heidelberg University and Heidelberg University Hospital - Institute for Computational Biomedicine

Grabengasse 1
Heidelberg, 69117
Germany

Klaus-Peter Knobeloch

University of Freiburg - Center for Basics in NeuroModulation (NeuroModulBasics) ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

University of Freiburg - Institute of Neuropathology ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Thomas Blank

University of Freiburg - Institute of Neuropathology ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Robert Thimme

University Medical Center Freiburg - Clinic for Internal Medicine II

Fahnenbergplatz
Freiburg, D-79085
Germany

Markus Glatzel

University Medical Center Hamburg-Eppendorf - Institute of Neuropathology

Hamburg
Germany

Marco Prinz

University of Freiburg - Institute of Neuropathology ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

Bertram Bengsch (Contact Author)

University Medical Center Freiburg - Clinic for Internal Medicine II ( email )

Fahnenbergplatz
Freiburg, D-79085
Germany

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