Single-nucleus transcriptome analysis of human brain immune response in patients with severe COVID-19

Genome Med. 2021 Jul 19;13(1):118. doi: 10.1186/s13073-021-00933-8.


Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been associated with neurological and neuropsychiatric illness in many individuals. We sought to further our understanding of the relationship between brain tropism, neuro-inflammation, and host immune response in acute COVID-19 cases.

Methods: Three brain regions (dorsolateral prefrontal cortex, medulla oblongata, and choroid plexus) from 5 patients with severe COVID-19 and 4 controls were examined. The presence of the virus was assessed by western blot against viral spike protein, as well as viral transcriptome analysis covering > 99% of SARS-CoV-2 genome and all potential serotypes. Droplet-based single-nucleus RNA sequencing (snRNA-seq) was performed in the same samples to examine the impact of COVID-19 on transcription in individual cells of the brain.

Results: Quantification of viral spike S1 protein and viral transcripts did not detect SARS-CoV-2 in the postmortem brain tissue. However, analysis of 68,557 single-nucleus transcriptomes from three distinct regions of the brain identified an increased proportion of stromal cells, monocytes, and macrophages in the choroid plexus of COVID-19 patients. Furthermore, differential gene expression, pseudo-temporal trajectory, and gene regulatory network analyses revealed transcriptional changes in the cortical microglia associated with a range of biological processes, including cellular activation, mobility, and phagocytosis.

Conclusions: Despite the absence of detectable SARS-CoV-2 in the brain at the time of death, the findings suggest significant and persistent neuroinflammation in patients with acute COVID-19.

Keywords: Choroid plexus; Gene expression; Microglia; Neuroinflammation; Prefrontal cortex; SARS-CoV-2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / metabolism*
  • COVID-19 / immunology*
  • Choroid Plexus / metabolism
  • Gene Expression
  • Gene Expression Profiling / methods*
  • Gene Regulatory Networks
  • Humans
  • Immunity / genetics*
  • Immunity / immunology*
  • Inflammation
  • Microglia
  • Prefrontal Cortex / metabolism
  • SARS-CoV-2 / genetics
  • Transcriptome*