TY - JOUR
T1 - Single-nucleus transcriptome analysis of human brain immune response in patients with severe COVID-19
AU - Fullard, John F.
AU - Lee, Hao Chih
AU - Voloudakis, Georgios
AU - Suo, Shengbao
AU - Javidfar, Behnam
AU - Shao, Zhiping
AU - Peter, Cyril
AU - Zhang, Wen
AU - Jiang, Shan
AU - Corvelo, André
AU - Wargnier, Heather
AU - Woodoff-Leith, Emma
AU - Purohit, Dushyant P.
AU - Ahuja, Sadhna
AU - Tsankova, Nadejda M.
AU - Jette, Nathalie
AU - Hoffman, Gabriel E.
AU - Akbarian, Schahram
AU - Fowkes, Mary
AU - Crary, John F.
AU - Yuan, Guo Cheng
AU - Roussos, Panos
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Choroid plexus
KW - Gene expression
KW - Microglia
KW - Neuroinflammation
KW - Prefrontal cortex
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85110687282&partnerID=8YFLogxK
U2 - 10.1186/s13073-021-00933-8
DO - 10.1186/s13073-021-00933-8
M3 - Article
C2 - 34281603
AN - SCOPUS:85110687282
SN - 1756-994X
VL - 13
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 118
ER -