Journal Article

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

Fullard, John F., Fowkes, Mary, Lee, Hao-Chih, Hoffman, Gabriel E., Shao, Zhiping, Purohit, Dushyant P., Jette, Nathalie, Roussos, Panos, Suo, Shengbao, Yuan, Guo-Cheng, Ahuja, Sadhna, Akbarian, Schahram, Corvelo, André, Wargnier, Heather, Voloudakis, Georgios, Javidfar, Behnam, Tsankova, Nadejda M., Jiang, Shan, Zhang, Wen, Woodoff-Leith, Emma, Peter, Cyril, Crary, John F.

2021

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Analysis / Annotations / Autopsy / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Brain / Brain - metabolism / Cancer Research / Care and treatment / Choroid plexus / Choroid Plexus - metabolism / Cognitive ability / Coronaviruses / COVID-19 / COVID-19 - immunology / Dissection / Gene Expression / Gene Expression Profiling - methods / Gene Regulatory Networks / Genes / Genetic transcription / Genomes / Genomics / Health aspects / Human Genetics / Humans / Immune response / Immunity - genetics / Immunity - immunology / Inflammation / Macrophages / Medicine/Public Health / Medulla oblongata / Metabolomics / Microglia / Monocytes / Neuroinflammation / Phagocytosis / Prefrontal cortex / Prefrontal Cortex - metabolism / Proteins / RNA / RNA sequencing / SARS-CoV-2 / SARS-CoV-2 - genetics / Serotypes / Severe acute respiratory syndrome / Severe acute respiratory syndrome coronavirus 2 / snRNA / Spike protein / Stromal cells / Systems Biology / Temporal lobe / Transcription / Transcription factors / Transcriptome / Transcriptomes / Tropism