Neurological complications are common in COVID-19 patients. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been detected in patients’ brain tissues, its entry routes and resulting consequences are not well understood. Here, we report that the blood-brain barrier (BBB) and its microenvironment show pronounced upregulation of interferon signaling pathways in fatal COVID-19. Moreover, human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) were susceptible to SARS-CoV-2 infection and recapitulated the 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 transcytosis of the virus across the BBB in vitro . SARS-CoV-2 entry into BCECs could be reduced by anti-spike-, anti-ACE2- and anti-NRP1-specific antibodies or the TMPRSS2 inhibitor nafamostat. Together, our data provide direct evidence for SARS-CoV-2 brain entry across the BBB resulting in an increase in interferon signaling.
Keywords: SARS-CoV-2, COVID-19, blood-brain barrier, neurovascular unit, hiPSC, infection model
Krasemann, Susanne and Haferkamp, Undine and Pfefferle, Susanne and Woo, Marcel Seungso and Heinrich, Fabian and Schweizer, Michaela and Appelt-Menzel, Antje and Barenberg, Janica and Leu, Jennifer and Hartmann, Kristin and Thies, Edda and Littau, Jessica Lisa and Sepulveda-Falla, Diego and Zhang, Liang and Ton, Kathy and Liang, Yan and Matschke, Jakob and Ricklefs, Franz and Sauvigny, Thomas and Sperhake, Jan and Fitzek, Antonia and Gerhartl, Anna and Brachner, Andreas and Franzenburg, Sören and Franke, Andre and Moese, Stefan and Müller, Franz-Josef and Geisslinger, Gerd and Claussen, Carsten and Kannt, Aimo and Zaliani, Andrea and Gribbon, Philip and Ondruschka, Benjamin and Neuhaus, Winfried and Friese, Manuel A. and Glatzel, Markus and Pless, Ole, The Blood-Brain Barrier is Dysregulated in COVID-19 and Serves as a CNS Entry Route for SARS-CoV-2. Available at SSRN: https://ssrn.com/abstract=3828200 or http://dx.doi.org/10.2139/ssrn.3828200
This version of the paper has not been formally peer reviewed.
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