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

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.

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

Authors

Andre Corvelo

Other Contributors

John F Fullard^#^{1 2 3 4 5}, Hao-Chih Lee^#^{1 2 3 4 5}, Georgios Voloudakis^1 2 5, Shengbao Suo⁶, Behnam Javidfar^2 5, Zhiping Shao^{1 2 3 4 5}, Cyril Peter^2 5, Wen Zhang^{1 2 3 4 5}, Shan Jiang^{1 2 3 4 5}, André Corvelo⁷, Heather Wargnier^8 9 10, Emma Woodoff-Leith^8 9 10, Dushyant P Purohit^5 8, Sadhna Ahuja⁸, Nadejda M Tsankova^8 9, Nathalie Jette^11 12, Gabriel E Hoffman^{1 2 3 4 5}, Schahram Akbarian^2 5, Mary Fowkes⁸, John F Crary^8 9 10, Guo-Cheng Yuan^4 13, Panos Roussos^{14 15 16 17 18 19}

Affiliations

¹Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
²Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
³Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
⁴Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
⁵Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
⁶Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁷New York Genome Center, New York, NY, USA.
⁸Department of Pathology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
⁹Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
¹⁰Neuropathology Brain Bank & Research Core, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
¹¹Department of Neurology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
¹²Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
¹³Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
¹⁴Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
¹⁵Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
¹⁶Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
¹⁷Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
¹⁸Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029, USA.
¹⁹Mental Illness Research Education and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, 10468, NY, USA.

^#Contributed equally.

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