SARS-CoV-2 Poorly Replicates in Cells of the Human Blood-Brain Barrier Without Associated Deleterious Effects

Abstract

Various neurological symptoms have been associated to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection including headache, fever, anosmia, ageusia, but also, encephalitis, Guillain-Barre syndrome and ischemic stroke. Responsible for the current coronavirus disease (COVID-19) pandemic, SARS-CoV-2 may access and affect the central nervous system (CNS) by several pathways such as axonal retrograde transport or through interaction with the blood-brain barrier (BBB) or blood-cerebrospinal fluid (CSF) barrier. Here, we explored the molecular and cellular effects of direct SARS-CoV-2 infection of human BBB cells. We observed low replication of SARS-CoV-2 that was accompanied by very moderate inflammatory response. Using a human in vitro BBB model, we also described low replication levels without strong inflammatory response or modulation of endothelium integrity. Finally, using serum samples from COVID-19 patients, we highlighted strong concentrations of pro-inflammatory factors that did not perturb BBB integrity after short term exposure. Altogether, our results show that the main mechanism of brain access following SARS-CoV-2 infection does not seem to be directed by brain infection through endothelial cells.

COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences

“…The resulting shift towards lower molecular weight hyaluronic acid fragments in the medium reduced barrier properties of the endothelial cells ( Queisser et al, 2021 ). In contrast, the permeability of brain-like endothelial cells was not changed after 48 h treatment with plasma from COVID-19 patients that developed severe disease ( Constant et al, 2021 ). In severe COVID-19, platelet hyperactivation is often observed ( Manne et al, 2020 ; Zaid et al, 2020 ), and treatment of endothelial cells with supernatant of activated platelets induced a strong upregulation of pro-inflammatory and procoagulant pathways as assessed by RNAseq.…”

“…Moreover, in an established human blood-brain barrier model where CD34 + umbilical cord blood-derived endothelial cells were grown on filter inserts in co-culture with bovine pericytes, no productive infection of endothelial cells was detected. Also, no impairment of their barrier function was observed, and an inflammatory response remained absent, indicating that these brain-like endothelial cells were not affected by infection with SARS-CoV-2 ( Constant et al, 2021 ). In contrast, although active viral replication remained absent in primary lung endothelial cells, an inflammatory response was induced during SARS-CoV-2 infection, indicating that there is an interaction between primary lung endothelial cells and the virus ( Caccuri et al, 2021 ).…”

“…Moreover, iPSC-derived blood vessel organoids containing endothelial cells and pericytes were infected with SARS-CoV-2 and viral replication could be observed on a transcriptional level after 3- and 6-days post infection ( Monteil et al, 2020 ) ( Figure 3 ). Primary human pericytes and astrocytes were directly infected without exhibiting any successful viral replication and cytopathogenic effects ( Constant et al, 2021 ). Altogether, more research should be performed on cells that are present in the vascular wall and perivascular locations since these can have an immense effect on the surrounding tissue, including endothelial cells.…”

SARS-CoV-2 and type I interferon signaling in brain endothelial cells: Blurring the lines between friend or foe

“…Furthermore, their specific findings on type I interferon signatures (IFN-I) have already been reported in studies on interactions between SARS-CoV-2 and brain endothelial cells. These prior studies, which were not cited in the Krasemann paper, both provide support for and indicate caveats in their study, effectively constituting its context ( Constant et al., 2021 ). In its current form, with these prior studies remaining insufficiently discussed by Krasemann et al., their model appears somewhat preliminary.…”

“…In contrast to Krasemann et al.’s findings, Wenzel and colleagues report that during SARS-CoV-2 infection of brain endothelial cells, interactions between its main protease (M pro ) and the NF-kappa-B essential modulator (NEMO) result in apoptosis and subsequent BBB disruption ( Wenzel et al., 2021 ). Furthermore, unless a consistent inflammatory signal is present, SARS-CoV-2 may not productively replicate within brain endothelial cells and subsequently cross the BBB ( Constant et al., 2021 ). This complex relationship is reflected in ex vivo findings linking endothelial and brain injury with inflammation in COVID-19 ( Savarraj et al., 2021 ).…”