No abstract

COVID-19, which is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), has resulted in devastating morbidity and mortality worldwide due to lethal pneumonia and respiratory distress. In addition, the central nervous system (CNS) is well documented to be a target of SARS-CoV-2, and studies detected SARS-CoV-2 in the brain and the cerebrospinal fluid of COVID-19 patients. The blood–brain barrier (BBB) was suggested to be the major route of SARS-CoV-2 infection of the brain. Functionally, the BBB is created by an interactome between endothelial cells, pericytes, astrocytes, microglia, and neurons, which form the neurovascular units (NVU). However, at present, the interactions of SARS-CoV-2 with the NVU and the outcomes of this process are largely unknown. Moreover, age was described as one of the most prominent risk factors for hospitalization and deaths, along with other comorbidities such as diabetes and co-infections. This review will discuss the impact of SARS-CoV-2 on the NVU, the expression profile of SARS-CoV-2 receptors in the different cell types of the CNS and the possible role of aging in the neurological outcomes of COVID-19. A special emphasis will be placed on mitochondrial functions because dysfunctional mitochondria are also a strong inducer of inflammatory reactions and the “cytokine storm” associated with SARS-CoV-2 infection. Finally, we will discuss possible drug therapies to treat neural endothelial function in aged patients, and, thus, alleviate the neurological symptoms associated with COVID-19.

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 exposure 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-exposed cultures displayed increased immunoreactivity for cleaved caspase-3, an indicator of apoptotic cell death, tight junction protein expression, and immunolocalization. Transcriptomic profiling of SARS-CoV-2-challenged 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.

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.

Congenital toxoplasmosis is a parasitic disease that occurs due vertical transmission of the protozoan Toxoplasma gondii (T. gondii) during pregnancy. The parasite crosses the placental barrier and reaches the developing brain, infecting progenitor, glial, neuronal and vascular cell types. Although the role of Radial glia (RG) neural stem cells in the development of the brain vasculature has been recently investigated, the impact of T. gondii infection in these events is not yet understood. Herein, we studied the role of T. gondii infection on RG cell function and its interaction with endothelial cells. By infecting isolated RG cells with T. gondii tachyzoites, we observed reduced cell proliferation and neurogenesis without affecting gliogenesis levels. Conditioned medium (CM) from RG control cultures increased ZO-1 and β-catenin protein levels and organization on endothelial bEnd.3 cells membranes, which was completely impaired by CM from infected RG, resulting in decreased transendothelial electrical resistance (TEER). Cytokine Bead Array and ELISA assays revealed the presence of increased levels of the pro-inflammatory cytokine IL-6 and reduced levels of anti-inflammatory cytokine TGF-β1 in CM from T.gondii-infected RG cells. Treatment with recombinant TGF-β1 concomitantly with CM from infected RG cultures led to restoration of ZO-1 staining in bEnd.3 cells. Our results suggest that infection of RG cells by T. gondii modulate cytokine secretion, which might contribute to endothelial loss of barrier properties, thus leading to impairment of neurovascular interaction establishment.

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.