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 role of virus tropism remain largely unclear. Here, we deeply interrogated brain stem olfactory bulb in patients with imaging mass cytometry to understand local response at a spatially resolved, high-dimensional single-cell level. We observed significant activation CNS identified distinct phenotypes T cells microglial clusters, presence specific anatomical regions context-specific interactions. Microglial nodules perivascular cell clusters constitute key sites response, viral antigen present ACE2-expressing compartment. Disease-associated neuroinflammation is associated astrogliosis severe axonal damage as structural basis for neurologic deficits. Finally, identify compartment- cluster-specific checkpoints that be targeted future therapeutic interventions. Funding: This project was supported by grants from Deutsche Forschungsgemeinschaft (DFG, GermanResearch Foundation) (SFB 992, SFB1160, SFB/TRR167, SFB/TRR179, German Excellency strategyCIBSS - EXC-2189– Project ID390939984) special research funds Ministry Science, Research Art Baden-Wuerttemberg dedicated “COVID-19 research” “Neuroinflammation”.B.B. further DFG grant BE-5496/5-1 M.P. Sobek Foundation, Ernst-Jung Reinhart-Koselleck-Grant Gottfried Wilhelm Leibniz-Prize.H.E.M. ME-3644/5-1. Ethical Approval: analyses were performed approval Institutional Review Boards (Ethic Committee Albert-Ludwigs-University, Freiburg: 322/20, 10008/09; Ethics Hamburg Chamber Physicians: WF-051/20, PV7311). study agreement principles expressed Declaration Helsinki (2013). Conflict Interest: None declare.