The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2
Гематоэнцефалический барьер нарушается при COVID-19 и служит путем проникновения SARS-CoV-2 в центральную нервную систему
2022-01-20
SCID: 54.1/sds2n7q5
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SARS-CoV-2blood-brain barrierbrain capillary endothelial cellsinterferon signalingtranscellular viral transport
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Abstract (AI)
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.
Key Findings
1
Fatal COVID-19 is associated with pronounced upregulation of interferon signaling pathways in the neurovascular unit.
2
Human induced pluripotent stem cell-derived brain capillary endothelial-like cells are susceptible to SARS-CoV-2 infection and reproduce transcriptional changes observed in vivo.
3
SARS-CoV-2 crosses the endothelial blood-brain barrier model through basolateral release after apical infection, despite preserved paracellular tightness, indicating transcellular transport and active replication.
4
SARS-CoV-2 entry into brain endothelial-like cells is reduced by antibodies against spike, ACE2, or NRP1, and by the TMPRSS2 inhibitor nafamostat.
5
The findings support the blood-brain barrier as a route for SARS-CoV-2 entry into the central nervous system, accompanied by increased interferon signaling.
Research Object
The blood-brain barrier, modeled by human iPSC-derived brain capillary endothelial-like cells, during SARS-CoV-2 infection
Research Subject
SARS-CoV-2 susceptibility, transcellular transport across the barrier, and infection-associated interferon signaling
Publication Details
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2022-01-20
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