Fig. 1

SARS-CoV-2 invades the brain and infects brain vascular endothelial cells, leading to brain damage in animal models. a Viral load in lung and brain tissues of SARS-CoV-2-challenged K18-hACE2 mice (n = 6/group) and hamsters (n = 9/group) was detected by qRT-PCR. b Distribution of SARS-CoV-2 spike protein (S) in SARS-CoV-2-challenged K18-hACE2 mice detected by fluorescence in situ hybridization (FISH). c–e FISH images showing SARS-CoV-2 co-localized with ACE2, distributed in vascular endothelial cells and in the perivascular spaces (white arrows) in the cortex of infected K18-hACE2 mice. Images of H&E-stained sequential sections subjected to FISH (e) showing homogeneous red-staining exudate in perivascular space (black arrow). f Representative H&E-stained image showing vasculitis in the brain of infected K18-hACE2 mice. Black arrow: inflammatory cell infiltration. g, h Representative images showing SARS-CoV-2-S mainly co-localized with NeuN, a marker for neurons, rather than GFAP, a marker for astrocytes in infected K18-hACE2 mice using FISH. i, j Representative images of H&E-stained neurons showing denatured and necrotic cells (red arrowhead) in the cortex layer IV of infected K18-hACE2 mice. k Representative ultrastructural images showing death cells undergoing pyknosis and virus-like particles (red arrow) l in the cortex of infected K18-hACE2 mice. m Pyknotic cells were also found in the cortex of infected hamsters. n Representative ultrastructural images showing enlarged mitochondria at high density (asterisk) and giant mitochondria o (red arrowhead) in the cortex of infected hamsters. Yellow arrow: normal mitochondria. p–s Representative H&E-stained images showing vascular events in the brains of infected hamsters, including perivascular inflammatory cell infiltration (p), focal hemorrhage (q), and enlarged perivascular spaces (r). s, t TUNEL-stained images showing apoptotic cells in the cortex of one infected hamster. t High magnification view of the zone delimited by the rectangle of panel s. Scale: b 1 mm; c–f, h, j, q, r, t 50 μm; g, i, p 100 μm; k, m 2 μm; l 200 nm; n, o 1 μm; s 500 μm