BREAKING! German Scientists Discover That SARS-CoV-2 Main Protease Mpro Causes Microvascular Brain Pathology!
: A new study by researchers from the Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck-Germany has alarmingly found that the SARS-CoV-2 main protease mpro causes microvascular brain pathology cleaving NEMO (The essential modulator of nuclear factor-κB) in brain endothelial cells!
The study findings were published in the peer reviewed journal: Nature Neuroscience. https://www.nature.com/articles/s41593-021-00926-1
To date, it has been found that a considerable proportion of patients, up to 84% of those with severe COVID-19, show neurological signs and symptoms including anosmia, epileptic seizures, strokes, loss of consciousness and confusion. Typically, COVID-19 can present with the clinical picture of encephalopathy. Beyond 4 weeks after onset, the post-acute COVID-19 syndrome includes cognitive impairment and a range of psychiatric symptoms and may affect up to 76% of patients. https://pubmed.ncbi.nlm.nih.gov/32294339/
Though a direct infection of the brain remains a matter of debate, SARS-CoV-2 viral genomes were detected in the brain and cerebrospinal fluid (CSF) of some patients, supporting the notion that SARS-CoV-2 gains access to the brain.
The viral RNA has been found in blood and virus-like particles or viral proteins in brain endothelial cells, suggesting that SARS-CoV-2 reaches the brain by a hematogenous route. In line with a vascular infection, endothelial cells in other organs have been identified as targets of SARS-CoV-2 infection. In patients with COVID-19, magnetic resonance imaging detected lesions that are compatible with a cerebral small-vessel disease and with a disruption of the blood–brain barrier (BBB) Autopsy studies have confirmed this interpretation. However, the microvascular pathology and the underlying mechanisms in COVID-19 are still unclear.
study team describes structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology.
In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, the st
udy team found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries.
The study team obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice.
The study findings alarmingly confims that Mpro
of SARS-CoV-2 cleaves host cell NEMO with high efficiency. In infected cells, Mpro
is located in the cytosol and nucleus, where NEMO is also present.
This may benefit the virus by preventing the induction of antiviral type I interferons that depends on NEMO. Indeed, levels of type I interferons are low or absent in the peripheral blood of patients with COVID-19.
Cleaving NEMO is also a strategy used by other viruses.
However, the tropism of SARS-CoV-2 is likely to limit NEMO inactivation to specific cell types. Accordingly, some NF-κB-dependent cytokines, such as TNF and IL-6, are highly upregulated, indicating that the cells of origin have escaped NEMO inactivation.
In addition to its central role in immunity, NEMO supports the survival of some but not all cell types. While neurons, glia and endothelial cells of peripheral vessels seem to resist NEMO deficiency or are even protected by it against inflammatory stimuli, the survival of other cells, including brain endothelial cells, is supported by NEMO.
The study findings suggest that, in COVID-19, brain endothelial cells are at disproportionate risk when being infected by SARS-CoV-2 because of their dependence on NEMO activity for survival.
It should be noted that Cleavage of NEMO by Mpro
mimics the genetic disease incontinentia pigmenti
that is caused by inactivating mutations in the NEMO (IKBKG
) gene. In the latter condition, patients suffer from a mix of neurological symptoms, such as encephalopathy, stroke and seizures that resemble neurological manifestations of COVID-19.
In the study, the absence of NEMO in mice induced a loss of endothelial cells and microvascular pathology. Subsequently, patchy hypoxia developed in the brain and the BBB became leaky. In parenchymal cells, a prominent upregulation of GFAP indicated the activation of astrocytes, in line with the finding that GFAP concentrations are elevated in the blood of patients with COVID-19. An increased BBB permeability and astrocyte activation may cause epileptic seizures in patients with COVID-19 as in incontinentia pigmenti
Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology.
The study findings also suggest that RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
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