Brain fog and epileptic seizures: is Covid-19 to blame?

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Brain fog is a commonly reported neurological symptom of Covid-19.

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Since the start of the Covid-19 pandemic, there have been reports of patients with symptoms related to the nervous system and the brain. These neurological symptoms have been seen both during and after infection and can range from fatigue and brain fog to seizures and strokes. In many cases, the underlying mechanisms are not yet fully understood.

A recent report by an international group of researchers, led by Jan Wenzel, Josephine Lampe and Helge Mller-Fielitz from the University of Lbeck, Germany, begins to provide some answers. Their findings are twofold: first, they show that Covid-19 patients exhibit structural damage to small blood vessels in the brain, and second, they propose that it is caused by the main SARS-COV-2 protease, Mpro, killing endothelium. cells.

All of our blood vessels are lined with a thin layer called the endothelium. This layer helps regulate what goes in and out of the bloodstream. Endothelial cells also play an important role in the formation of blood vessels, providing signals that help build the walls of blood vessels. As a result, the death of endothelial cells can cause what are called filarial vessels. These are dysfunctional remnants of capillaries that cannot maintain blood flow. High levels of filarial vessels are often an indicator of some sort of brain pathology.

To test the association between the accumulation of string vessels and Covid-19, Wenzel et al. studied the frontal cortex of 17 people, all over the age of sixty, who died of the disease. They compared these brain samples to those from 23 control subjects, of similar age, who died from other causes unrelated to Covid-19. As expected, the researchers noticed a significant increase in filarial vessels in patients infected with SARS-COV-2, an increase that remained even after adjusting for comorbidities and gender.

The same goes for the mouse and hamster models (Figure 1).

FIGURE 1. Significantly more filarial vessels (yellow arrowheads) in mice infected with SARS-CoV-2 and … [+] hamsters (right) than in the control group (left).

From: The major protease Mpro of SARS-CoV-2 causes microvascular brain pathology by cleaving NEMO in endothelial cells of the brain WENZEL ET AL., 2021

The researchers also found cells in microvessels in the brain that expressed active caspase-3. When a cell dies or has been damaged beyond repair, it must be destroyed and disposed of. This process is called apoptosis. Caspase-3, an executioner caspase, plays a vital role in this process by breaking down cell structures. The presence of caspase-3 therefore supports the idea that filarial vessels form as a result of the death of endothelial cells.

So, there is some evidence for filarial vessel formation and endothelial cell death in the brains of Covid-19 patients, but how does SARS-CoV-2 cause this?

Wenzel et al. first turned to the brain endothelial cells themselves; Since these showed signs of cell death during infection, this would suggest that they may have been directly infected with SARS-CoV-2.

A good way to check if infection is possible is to look for the proteins that SARS-CoV-2 uses to bind to and possibly enter our cells.

And, despite being primarily located in other parts of the blood vessels, the researchers actually found the proteins required to be expressed in endothelial cells in the brain. Illustrating that, at least in principle, infection with SARS-CoV-2 can occur.

Moving from principle to practice, Wenzel et al. decided to expose an in vitro model of cultured brain endothelial cells to SARS-CoV-2. Indeed, the researchers quickly located the Spike (S) protein of SARS-CoV-2s used by the virus to bind to host cells around the nuclei of endothelial cells.

But the question remains, by what mechanism does SARS-CoV-2 cause endothelial cell death?

Here Wenzel et al. turned to a protein called the essential modulator NF-kappa-B (NEMO). NEMO plays a key role in the activation of NF-kappaB, which itself plays a key role in regulating the immune response to infection. Importantly, NEMO is also integral to the survival of certain cells. Since SARS-CoV-2 always tries to stay ahead of our immune response, researchers have speculated that it may split, and thus inactivate, NEMO to save more time. It’s possible, they believed, that brain endothelial cell death could occur as a byproduct of this immune suppression tactic.

Confirming part of their hunch, the researchers found an increased presence of cleaved NEMO in the brain cells of patients infected with SARS-CoV-2, compared to the control group.

Then, suspecting that it might have something to do with proteases, Wenzel et al. exposed brain endothelial cells derived from mice to two SARS-CoV-2 proteases: the main protease (Mpro) and the papain-like protease. Indeed, it turned out that Mpro cleaved NEMO in the endothelial cells of the brain of mice. The same is true for NEMO in endothelial cells of the human brain.

Not yet satisfied, Wenzel et al. also wanted confirmation that NEMO cleavage actually results in endothelial cell death. To do this, they inserted Mpro into endothelial cells in the human brain. As expected, these cells more frequently exhibited markers indicative of cell death than those not exposed to Mpro. Endothelial cells exposed to an inactivated form of Mpro, in contrast, were spared by NEMO cleavage and subsequent cell death.

The nail in the coffin: Within two weeks, live mice exposed to Mpro developed a pathology of the filarial vessels indistinguishable from that of Covid-19 patients. Those exposed to inactivated Mpro were doing perfectly well.

But there is also good news. Wenzel et al. discovered that the cleavage of NEMO induces the death of endothelial cells via an enzyme called RIPK3. When this enzyme is deactivated, death of endothelial cells is avoided and, therefore, microvascular pathology is avoided. This opens the door to new treatments and interventions, which could help avoid neurological symptoms reported by a rapidly growing Covid-19 patient list.

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