The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2

Abstract

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.

Graphical abstract

Abstract

In this article, Pless and colleagues show upregulation of IFNγ signaling in the neurovascular unit of the brain in fatal COVID-19. They show that an hiPSC-derived brain capillary endothelial cell model can be infected with SARS-CoV-2, resulting in similar expression changes, viral replication, and release while endothelial cell integrity is maintained. Infection can be prevented by antibodies or protease inhibitors.