Abstract
BackgroundCoronavirus 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.MethodsThree 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.ResultsQuantification 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.ConclusionsDespite 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.
Highlights
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 note that all COVID-19 cases were classified as severe; the clinical characteristics of donors are detailed in Additional file 1: Table S1
For the immunoblotting and SARS-CoV-2-targeted RNA-seq assay, we included a single dissection with the exception of the prefrontal cortex (PFC), from which we included separate dissections of cortical gray matter and white matter
Summary
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. Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently the most urgent health care issue in the world. Studying neurological disease in COVID-19 patients presents several challenges, including only a subset of the patient population displaying neurological symptoms, an inability to sample CNS tissues directly in living individuals, and difficulties in distinguishing direct neuro-invasion from systemic viremia within the brain. Overall, existing studies provide multiple mechanisms through which SARS-CoV-2 affects the human brain, including direct invasion and infection of specific types of neurons and glia, in addition to endothelial injury and vascular coagulopathy and diffuse neuroinflammatory processes or systemic inflammatory and hypercoagulable states
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