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

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: 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.