SARS-CoV-2 infection of human brain microvascular endothelial cells leads to inflammatory activation through NF-κB non-canonical pathway and mitochondrial remodeling

Abstract

Neurological effects of COVID-19 and long-COVID-19 as well as neuroinvasion by SARS-CoV-2 still pose several questions and are of both clinical and scientific relevance. We described the cellular and molecular effects of the human brain microvascular endothelial cells (HBMECs) in vitro infection by SARS-CoV-2 to understand the underlying mechanisms of viral transmigration through the Blood-Brain Barrier. Despite the low to non- productive viral replication, SARS-CoV-2-infected cultures displayed increased apoptotic cell death and tight junction protein expression and immunolocalization. Transcriptomic profiling of infected cultures revealed endothelial activation via NF-κB non-canonical pathway, including RELB overexpression, and mitochondrial dysfunction. Additionally, SARS-CoV-2 led to altered secretion of key angiogenic factors and to significant changes in mitochondrial dynamics, with increased mitofusin-2 expression and increased mitochondrial networks. Endothelial activation and remodeling can further contribute to neuroinflammatory processes and lead to further BBB permeability in COVID-19.

ACE-2, TMPRSS2, and Neuropilin-1 Receptor Expression on Human Brain Astrocytes and Pericytes and SARS-CoV-2 Infection Kinetics

“…Pericytes expressed a 3.4-fold higher number of TMPRSS-2 mRNA copies (Figure 2B) compared to astrocytes. TMPRSS-2 mRNA expression in human brain cells (hBMVECs) mirrors the finding by Torices et al [39]. Thus, our results not only affirm the earlier study findings but provide additional data on the mRNA level expression of TEMPRSS-2 in brain cells.…”

Role of aging in Blood–Brain Barrier dysfunction and susceptibility to SARS-CoV-2 infection: impacts on neurological symptoms of COVID-19

“…We have recently described that BBB cells display a unique profile of SARS-CoV-2 receptors, with differential expression of molecules such as ACE2, TMPRSS2, ADAM17 and others in human BMECs, astrocytes, pericytes, microglia and neurons [26]. We have also demonstrated that SARS-CoV-2 leads to minimal productive infection on immortalized HMECs [27], although increased apoptosis and inflammation was triggered in infected cultures. Experimental infection of K18-hACE2 mice or hamsters led to effective infection of BMECs, despite no changes in tight junctions were observed [28].…”

“…Mitochondrial morphology is highly dynamic, being different and adjustable in each cell type and maintains a genetic and biochemical homogeneity by allowing for dilution of toxic superoxide species, mutant mtDNA, and repolarization of membranes during homeostasis, stress and inflammation [194][195][196][197]. Accordingly, we have recently shown that infection of HBMEC by SARS-CoV-2 leads to an inflammatory status with cytokine and chemokine production and remodeling of mitochondrial networks, with increased Mfn2 expression [27]. However, additional studies that focus on the role of host cell mitochondrial remodeling upon SARS-CoV-2 infection, including mitochondrial biogenesis and metabolic responses, remain to be elucidated.…”

Yellow Fever Virus Infection Alters Mitochondrial Network Dynamics

“…32,40 Similar results were found in ZIKV but not WNV infections. 32 Recently, MiNA analysis showed that direct exposure of human microvascular endothelial cells to SARS-CoV-2, in which the viral replication cycle is restricted, 41 led to a remodelling of mitochondrial networks by increasing the mitochondrial footprint and mitochondrial networks as determined by summed branch length analyses, 42 suggesting a hyperfused state. Overall, our data are more consistent with those from HCV studies but also suggest that MD may be selectively manipulated depending on the type of virus and likely cell type.…”