Assessing the impact of COVID-19 infection on the choroid plexus and frontal lobe at the single-nucleus level

Abstract

Five years after the COVID-19 pandemic’s onset in 2020, patients and healthcare systems worldwide continue to experience lingering impacts. One such impact is the detrimental effect of COVID-19 infection on neurological functioning. Recent research has suggested that although SARS-CoV-2 does not demonstrate neurotropism, peripheral SARS-CoV-2 infection may cause widespread neuroinflammation that drives neurological complications, such as ischemic stroke and chronic brain fog. It is unknown, however, which inflammatory signaling pathways are responsible for these outcomes, and specific CNS cell types impacted by peripheral SARS-CoV-2 infection have not yet been identified. Here, we integrate snRNA-Seq data from the choroid plexus and frontal lobe regions of post-mortem brain tissue from 12 severe COVID-19 patients and 18 control patients. By examining cell types in the CNS that are perturbed in COVID-19 patients, we provide evidence demonstrating that brain barrier cells, such as endothelial, epithelial, and ependymal cells, become inflamed in response to peripheral SARS-CoV-2 infection. Specifically, we use UCell scoring to identify significant TGF-β, IL6-JAK-STAT3, and IFN-γ inflammatory signatures in these cell populations in COVID-19 patients. Additionally, we use CellChat intercellular communication network analysis to infer significant intercellular interactions in COVID-19 infection, such as the propagation of IL16 and PTN inflammatory signals from brain barrier cells to neurons, glial cells, and immune-related populations in the brain parenchyma. We also utilize differential gene expression analysis to determine that glial cells in severe COVID-19 patients are characterized by pro-inflammatory gene expression profiles, and we identify differentially expressed genes, such as FTH1 in astrocytes, that may serve as potential therapeutic targets or as diagnostic biomarkers for COVID-19-related neurological complications. Finally, we use CellOracle GRN inference and network analysis to identify differences in GRN structures between cell clusters in COVID-19 patients and control individuals, and we observe decreased eigenvector centrality scores in COVID-19 GRNs for transcription factors NFE2, EGR1, and KLF2, which are crucial for inhibiting viral replication and maintaining the blood-brain barrier. Together, our results suggest that regulation of these genes and signaling pathways may constitute new therapeutic opportunities for COVID-19-related neurological complications and other neurological conditions that are characterized by increased neuroinflammation.No embargoAcademic Major: Neuroscienc