Dysregulation of brain and choroid plexus cell types in severe COVID-19

Though SARS-CoV-2 primarily targets the respiratory system, patients and survivors can suffer neurological symptoms. Yet, an unbiased understanding of the cellular and molecular processes affected in the brains of COVID-19 patients is still missing. Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease. Synaptic signaling of upper-layer excitatory neurons—evolutionarily expanded in humans and linked to cognitive function—are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later. Overall design: Single-nuclei RNA transcriptomes of prefrontal cortex and choroid plexi tissue obtained from post-mortem brains of COVID-19, Influenza, and non-viral control patients using the 10x Genomics Drop-seq gene expression kit (v3.1). Samples were sequenced at 150 bps paired-end configuration on a NovaSeq system. Index 1 contains sample indices (8 nts). Read 1 contains 10x cell barcode + UMI (28 nts). Read 2 contains the fragment insert (91 nts).