Spatial multiomics dissects the SARS-CoV-2-induced disruption of cell adhesion and immune dynamics in the human hippocampus

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological complications, yet the underlying mechanisms remain poorly understood. Here, we used an integrated spatial multiomics approach to investigate the effects of SARS-CoV-2 on human hippocampus–entorhinal cortex (HP–EC) tissues from autopsies of individuals with severe COVID-19. Our analysis revealed a cascade of pathological events initiated by viral infection. First, we found that SARS-CoV-2 preferentially infects neurons, with the highest viral loads in the dentate gyrus. Second, this infection led to significant reductions in key cell–cell adhesion proteins, including contactin-associated protein (CASPR), myelin basic protein (MBP), and zona occludens-1 (ZO-1), which collectively indicate compromised axoglial junctions and blood–brain barrier (BBB) integrity. Third, we identified a paradoxical immune landscape characterized by impaired immune surveillance, which involved reduced T cells and homeostatic microglia, coupled with focal reactive microgliosis. Fourth, spatial transcriptomics revealed upregulation of mitogen-activated protein kinase (MAPK)/Wnt stress-response pathways and downregulation of homeostatic functions in infected cells. Finally, we observed increased somatic proximity between neurons and vascular cells, indicating altered neurovascular architecture. Collectively, these findings provide a comprehensive spatial characterization of the pathological landscape in the human brain following SARS-CoV-2 infection. This work offers novel insights into COVID-19 neuropathology and highlights key molecular processes, such as the disruption of junctional proteins and immune surveillance pathways, that warrant further investigation as potential avenues for future therapeutic strategies to mitigate the long-term neurological consequences of the disease.