Krasemann, SusanneSusanneKrasemannHaferkamp, UndineUndineHaferkampPfefferle, S.S.PfefferleWoo, M.S.M.S.WooHeinrich, F.F.HeinrichSchweizer, M.M.SchweizerAppelt-Menzel, AntjeAntjeAppelt-MenzelCubukova, A.A.CubukovaBarenberg, J.J.BarenbergLeu, J.J.LeuHartmann, K.K.HartmannThies, E.E.ThiesLittau, J.L.J.L.LittauSepulveda-Falla, D.D.Sepulveda-FallaZhang, L.L.ZhangTon, K.K.TonLiang, Y.Y.LiangMatschke, J.J.MatschkeRicklefs, F.F.RicklefsSauvigny, T.T.SauvignySperhake, J.J.SperhakeFitzek, A.A.FitzekGerhartl, A.A.GerhartlBrachner, A.A.BrachnerGeiger, N.N.GeigerKönig, E.-M.E.-M.KönigBodem, J.J.BodemFranzenburg, S.S.FranzenburgFranke, A.A.FrankeMoese, S.S.MoeseMüller, F.-J.F.-J.MüllerGeisslinger, G.G.GeisslingerClaussen, C.C.ClaussenKannt, A.A.KanntZaliani, A.A.ZalianiGribbon, P.P.GribbonOndruschka, B.B.OndruschkaNeuhaus, W.W.NeuhausFriese, M.A.M.A.FrieseGlatzel, M.M.GlatzelPless, O.O.Pless2022-05-062022-05-062022https://publica.fraunhofer.de/handle/publica/41610610.1016/j.stemcr.2021.12.011Neurological 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.enblood-brain barrierCOVID-19human-induced pluripotent stem cells (hiPSC)infection modelneurovascular unitSARS-CoV-2666616journal article