Human brain microvascular endothelial cells exposure to SARS-CoV-2 leads to inflammatory activation through NF-κB non-canonical pathway and mitochondrial remodeling
Motta, CS; Torices, S; da Rosa, BG; et al., Viruses
Published
March 2023
Journal
Viruses
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 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.
Authors
Carolline Soares Motta, Silvia Torices, Barbara Gomes da Rosa, Anne Caroline Marcos, Liandra Alvarez-Rosa, Michele Siqueira, Thaidy Moreno-Rodriguez, Aline da Rocha Matos, Braulia Costa Caetano, Jessica Santa Cruz de Carvalho Martins, Luis Gladulich, Erick Loiola, Olivia R M Bagshaw, Jeffrey A Stuart, Marilda M Siqueira, Joice Stipursky, Michal Toborek, Daniel Adesse
Keywords
COVID-19; NF-κB signaling pathway; blood–brain barrier; endothelial activation; mitochondrial dynamics
Short Summary
Many people with COVID-19 experience brain-related symptoms like confusion, headaches, and difficulty thinking clearly. These problems can continue for months after infection as part of Long COVID. Scientists are working to understand why the virus affects the brain, even though it mainly attacks the lungs, heart, and intestines.
Researchers studied how SARS-CoV-2 affects the cells that line tiny blood vessels in the brain. These cells form a protective barrier between blood and brain tissue. The team exposed human brain blood vessel cells and African monkey kidney blood vessel cells to live SARS-CoV-2 virus in laboratory experiments. They wanted to see how the virus infects cells and get through the protective barrier into brain tissue. The researchers measured how the cells responded by looking at inflammation markers, changes in the structure of the protective barriers, and changes in the cells’ energy-producing structures called mitochondria, which help maintain the protective brain barrier.
The study found that exposure to SARS-CoV-2 triggered strong inflammation in brain blood vessel cells. The virus activated a specific inflammation pathway called NF-κB that isn't usually turned on in these cells. This led to increased production of inflammatory substances that could alter brain tissue. The researchers also discovered that the virus changed how mitochondria work in these cells. Mitochondria became longer and more connected to each other, which can happen when cells are under stress. These changes occurred even though the virus didn't directly infect or kill the brain blood vessel cells.
These findings help explain how COVID-19 might cause brain symptoms without the virus directly infecting brain cells. The inflammation and changes in mitochondria could disrupt the cellular structure of the protective barrier between blood and brain. This disruption might allow harmful substances to enter brain tissue and cause thinking and memory problems seen in people with COVID. Understanding these mechanisms is an important step toward developing treatments for the neurological symptoms of COVID.