Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T cell interactions

Schwabenland, Marius; Salié, Henrike; Tanevski, Jovan; Killmer, Saskia; Lago, Marilyn Salvat; Schlaak, Alexandra Emilia; Mayer, Lena; Matschke, Jakob; Püschel, Klaus; Fitzek, Antonia; Ondruschka, Ben; Mei, Henrik E.; Boettler, Tobias; Neumann-Haefelin, Christoph; Hofmann, Maike; Breithaupt, Angele; Genc, Nafiye; Stadelmann, Christine; Saez-Rodriguez, Julio; Bronsert, Peter; Knobeloch, Klaus-Peter; Blank, Thomas; Thimme, Robert; Glatzel, Markus; Prinz, Marco; Bengsch, Bertram

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stem and olfactory bulb in COVID-19 patients postmortem using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, blood-brain-barrier leakage) and detected viral antigen in ACE2 receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific microanatomic immune niches with context-specific cellular interactions enriched for activated CD8+ T cells. Altered brain T cell–microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.