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 - Funding Information:
We thank the patients and families who donated materials for these studies. We thank the members of the Roussos Laboratory for the thoughtful advice and critique and the computational resources and expertise provided by the Scientific Computing at the Icahn School of Medicine at Mount Sinai. This paper is dedicated to the memory of Mary Fowkes.
Funding Information:
Supported by the National Institute on Aging, NIH grants R01-AG067025 (to P.R.) and R01-AG065582 (to P.R.) and Mount Sinai COVID-19 seed fund 0285VV12 (to S.A.).
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 -