Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19

Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19. Yang, A. C., Kern, F., Losada, P. M, Maat, C. A, Schmartz, G., Fehlmann, T., Schaum, N., Lee, D. P, Calcuttawala, K., Vest, R. T, Gate, D., Berdnik, D., McNerney, M. W., Channappa, D., Cobos, I., Ludwig, N., Schulz-Schaeffer, W. J., Keller, A., & Wyss-Coray, T. bioRxiv, Cold Spring Harbor Laboratory, 2020.

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Though SARS-CoV-2 primarily targets the respiratory system, it is increasingly appreciated that patients may suffer neurological symptoms of varied severity. However, an unbiased understanding of the molecular processes across brain cell types that could contribute to these symptoms in COVID-19 patients is still missing. Here, we profile 47,678 droplet-based single-nucleus transcriptomes from the frontal cortex and choroid plexus across 10 non-viral, 4 COVID-19, and 1 influenza patient. We complement transcriptomic data with immunohistochemical staining for the presence of SARS-CoV-2. We find that all major cortex parenchymal and choroid plexus cell types are affected transcriptionally with COVID-19. This arises, in part, from SARS-CoV-2 infection of the cortical brain vasculature, meninges, and choroid plexus, stimulating increased inflammatory signaling into the brain. In parallel, peripheral immune cells infiltrate the brain, microglia activate programs mediating the phagocytosis of live neurons, and astrocytes dysregulate genes involved in neurotransmitter homeostasis. Among neurons, layer 2/3 excitatory neurons–evolutionarily expanded in humans–show a specific downregulation of genes encoding major SNARE and synaptic vesicle components, predicting compromised synaptic transmission. These perturbations are not observed in terminal influenza. Many COVID-19 gene expression changes are shared with those in chronic brain disorders and reside in genetic variants associated with cognitive function, schizophrenia, and depression. Our findings and public dataset provide a molecular framework and new opportunities to understand COVID-19 related neurological disease.Competing Interest StatementThe authors have declared no competing interest.

@article {Yang2020.10.22.349415,
	author = {Yang, Andrew Chris and Kern, Fabian and Losada, Patricia M and Maat, Christina A and Schmartz, Georges and Fehlmann, Tobias and Schaum, Nicholas and Lee, Davis P and Calcuttawala, Kruti and Vest, Ryan T and Gate, David and Berdnik, Daniela and McNerney, M. Windy and Channappa, Divya and Cobos, Inma and Ludwig, Nicole and Schulz-Schaeffer, Walter J. and Keller, Andreas and Wyss-Coray, Tony},
	title = {Broad transcriptional dysregulation of brain and choroid plexus cell types with COVID-19},
	elocation-id = {2020.10.22.349415},
	year = {2020},
	doi = {10.1101/2020.10.22.349415},
	publisher = {Cold Spring Harbor Laboratory},
	abstract = {Though SARS-CoV-2 primarily targets the respiratory system, it is increasingly appreciated that patients may suffer neurological symptoms of varied severity. However, an unbiased understanding of the molecular processes across brain cell types that could contribute to these symptoms in COVID-19 patients is still missing. Here, we profile 47,678 droplet-based single-nucleus transcriptomes from the frontal cortex and choroid plexus across 10 non-viral, 4 COVID-19, and 1 influenza patient. We complement transcriptomic data with immunohistochemical staining for the presence of SARS-CoV-2. We find that all major cortex parenchymal and choroid plexus cell types are affected transcriptionally with COVID-19. This arises, in part, from SARS-CoV-2 infection of the cortical brain vasculature, meninges, and choroid plexus, stimulating increased inflammatory signaling into the brain. In parallel, peripheral immune cells infiltrate the brain, microglia activate programs mediating the phagocytosis of live neurons, and astrocytes dysregulate genes involved in neurotransmitter homeostasis. Among neurons, layer 2/3 excitatory neurons--evolutionarily expanded in humans--show a specific downregulation of genes encoding major SNARE and synaptic vesicle components, predicting compromised synaptic transmission. These perturbations are not observed in terminal influenza. Many COVID-19 gene expression changes are shared with those in chronic brain disorders and reside in genetic variants associated with cognitive function, schizophrenia, and depression. Our findings and public dataset provide a molecular framework and new opportunities to understand COVID-19 related neurological disease.Competing Interest StatementThe authors have declared no competing interest.},
	URL = {https://www.biorxiv.org/content/early/2020/10/22/2020.10.22.349415},
	eprint = {https://www.biorxiv.org/content/early/2020/10/22/2020.10.22.349415.full.pdf},
	journal = {bioRxiv}
}

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