The coronavirus disease 2019 (COVID-19) pandemic has had a major impact on global businesses, education systems and travel. With a fatality rate of over 1% and up to 15% of cases becoming seriously ill, the sheer number of cases of COVID-19 has overwhelmed the healthcare systems of many countries around the world.
The neurological impact of COVID-19 was recognized early in the pandemic, with post-mortem examination of critically ill patients showing signs of vascular injury to the brain. However, the exact mode of injury remains unclear.
Study: How COVID-19 affects the brain’s microvessels. Image credit: Radiological Images / Shutterstock.com
A recent brain study looks at the effects of COVID-19 on the cerebral microvascular system.
Endothelial activation and blood-brain barrier
In the current study, expert commentary is provided on the description of neurovascular injury, inflammation, and complement activation in the brain. Here, the authors describe a strong increase in extravasated serum proteins, especially fibrinogen, indicating leakage at the blood-brain barrier (BBB).
Another important finding was the accumulation of platelets in brain tissue and the upregulation of platelet endothelial cell adhesion molecule 1 (PECAM-1). Other factors that activate the coagulation system are also increased.
This suggests that endothelial activation occurs within the blood vessels of the brain, thereby blocking and damaging the microvessels. This theory is supported by previous results reported by the same authors, where they report injured cerebral blood vessels in post-mortem samples, as well as other studies showing this type of injury in magnetic resonance imaging (MRI) results.
The presence of immune complexes in the vascular wall containing immunoglobulin G (IgG) and IgM, along with complement factors, suggests that complement activation has occurred in the brain. This adds to previous findings of complement activation in COVID-19.
Activated complement factor C5b-9 forms a membrane attack complex (MAC), which is compatible with endothelial cell death. Both endothelial activation and a leaky BBB allow immune cells to enter cells, as evidenced by the presence of CD3 and CD8+ T cells as well as CD68+ macrophages.
Interestingly, these infiltrates are only found around blood vessels and not in the brain itself, indicating that COVID-19 causes indirect neuronal and glial injury. The hindbrain presents the greatest impact, perhaps because its vessels are more sensitive to injury or because viral entry is easier in this region.
Neurophagy was also observed, thus indicating that some neurons died and were consumed by microglia.
Transcriptomics data were obtained from this region and added to current knowledge about brain involvement in COVID-19. To this end, it appears that in COVID-19, genes encoding permeability regulatory factors such as endothelial nitric oxide synthase (eNOS) show different levels of expression than in control patients.
Vascular injury in the brain
Previously, researchers had proposed that endothelial activation was due to activation of complement through the classical pathway in response to immune complexes. This caused the BBB to become permeable to immune cells.
Other studies have similarly demonstrated the presence of autoantibodies against vascular antigens, which are occasionally able to activate the endothelium, in the blood and cerebrospinal fluid of patients with severe and long-COVID-19.
Other sources of endothelial activation could be certain cytokines such as tumor necrosis factor (TNF) or interleukins that are at elevated levels during the “cytokine storm” seen in severe COVID-19. These cytokines are known to cause endothelial cells to adhere to blood cells, causing the BBB to become leaky.
Another potential explanation for the vascular injury observed in the brain of patients with COVID-19 is the direct effect of viral invasion of endothelial cells. This has been corroborated by previous studies reporting the presence of viral particles in the brain tissue and vascular cells of these patients.
Induction of apoptosis in infected lung macrophages after infection reduces the rate of viral replication in infected cells and is mediated by the formation of inflammasomes and subsequently followed by hyperinflammation arising from the resulting cytokine storm. This can also happen in the brain and could explain the permeability of the BBB.
Conclusions
The current study shows the importance of understanding the pathophysiology of organ dysfunction in COVID-19, which could cause both acute and post-COVID symptoms. For example, activation of neuronal glial cells could initiate chronic neurological symptoms, which could be mitigated by therapeutics specific to the vascular effects of the infection.
The study by Lee and colleagues is further evidence that SARS-CoV-2 infection impairs vascular function and provides valuable insight into the molecular players involved in the interaction between the vasculature and the immune system.”