The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2
Summary
Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected in patients' brain tissues, its entry routes and resulting consequences are not well understood. Here, we show a pronounced upregulation of interferon signaling pathways of the neurovascular unit in fatal COVID-19. By investigating the susceptibility of human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) to SARS-CoV-2 infection, we found that BCECs were infected and recapitulated transcriptional changes detected in vivo. While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active replication and transcellular transport of virus across the blood-brain barrier (BBB) in vitro. Moreover, entry of SARS-CoV-2 into BCECs could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for SARS-CoV-2 brain entry across the BBB resulting in increased interferon signaling. Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
| Authors | Krasemann S, Haferkamp U, Pfefferle S, Woo MS, Heinrich F, Schweizer M, Appelt-Menzel A, Cubukova A, Barenberg J, Leu J, Hartmann K, Thies E, Littau JL, Sepulveda-Falla D, Zhang L, Ton K, Liang Y, Matschke J, Ricklefs F, Sauvigny T, Sperhake J, Fitzek A, Gerhartl A, Brachner A, Geiger N, König EM, Bodem J, Franzenburg S, Franke A, Moese S, Müller FJ, Geisslinger G, Claussen C, Kannt A, Zaliani A, Gribbon P, Ondruschka B, Neuhaus W, Friese MA, Glatzel M, Pless O |
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| Journal | Stem cell reports |
| Publication Date | 2022 Feb 8;17(2):307-320 |
| PubMed | 35063125 |
| PubMed Central | PMC8772030 |
| DOI | 10.1016/j.stemcr.2021.12.011 |