The coronavirus SARS-CoV-2 has led to a worldwide pandemic. Beside respiratory symptoms, infected people may develop neurologic dysfunctions such as loss of smell and taste, also seizures, and stroke. Even after recovery, patients frequently suffer from neurologic manifestations including dizziness, headache, impaired consciousness, cerebrovascular disease, ataxia, seizure, vision impairment, and nerve pain. The molecular events leading to the sometimes severe neurologic complications seen in COVID-19 patients are currently not well understood. However, involvement of the immune system and/or the vasculature have been proposed. We and others could show that SARS-CoV-2 may enter the brain and the central nervous system (CNS); however, several entry routes into the CNS have been discussed. Using an advanced Blood Brain Barrier (BBB) model based on human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs), we showed that endothelial cells of the BBB can be infected by SARS-CoV-2. Moreover, we determined a significant upregulation of interferon-gamma signaling in infected BCECs. The latter was also detected in the neurovascular unit (NVU) in post mortem COVID-19 brain by spatial transcriptomics using the NanoString GeoMx Digital Spatial Profiler, which was confirmed on a protein level in tissue, in particular for Interferon Induced Transmembrane Proteins 1 and 2 (IFITM1/IFITM2), hinting at a molecular response to SARS-CoV-2 infection. Together, our data provide strong probability for SARS-CoV-2 brain entry across the BBB resulting in an increase in interferon signaling. Elucidating such mechanisms may finally lead to development of therapeutic approaches to ameliorate disease severity and improve survival of those affected with COVID-19.

Learning Objectives:

1. Explain which cells of the blood brain barrier are infected by SARS-CoV-2.

2. Discuss the significance of interferon-gamma signaling in human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) infected with SARS-CoV-2.

3. Describe how spatial transcriptomics can be used to study gene expression in FFPE tissue sections.