As the COVID-19 pandemic played out, it brought with it an intimidating roster of short and long-term symptoms of the deadly disease. Neurological symptoms were soon recognized, emerging within six months for one in three patients, but the exact mechanism through which the damage to the brain occurred was unclear. Now, new research published in the journal Nature Neuroscience outlines evidence for infection of the brain’s endothelial cells leading to cell death, vessel destruction, and the disruption of the blood-brain barrier – a semipermeable border that protects the brain. While it's apparent that the resulting damage can be catastrophic, the research also presents potential treatment pathways that could work as a preventative therapy for future patients.

COVID-19 is considered to be predominantly a respiratory disease causing a wide range of symptoms, some of which are secondary to respiratory failure or the inflammation triggered by pneumonia. Neurological symptoms include anosmia, epileptic seizures, strokes, loss of consciousness, and confusion, and some patients present with a clinical workup indicative of encephalopathy, a condition that means the brain isn’t functioning properly. Understanding how this damage to the brain occurs in patients with COVID-19 is crucial to ascertain if and how it can be prevented, treated, or cured.

In their investigations, the authors of this new paper established that COVID-19 patients whose disease had progressed to acute respiratory syndrome showed an increased number of string vessels, which are the empty basement membrane tubes left behind when capillaries are damaged and lost.

Using two animals models both involving mice, they were able to establish that infection of the brain’s endothelial cells was leading to this uptick in string vessels as a protease of SARS-CoV-2 – the pathogen that causes COVID-19 – called Mpro damages a modulate known as NEMO.

NEMO acts on nuclear factor-κB – a protein complex that controls DNA transcription, cytokine production, and is pivotal in cell survival. SARS-CoV-2 was therefore killing brain endothelial cells and bumping up the number of string vessels in mice as a result of the inactivation of NEMO. By ablating NEMO, Mpro also deletes receptor-interacting protein kinase Ripk3, which mediates cell death.

A genetic disease called incontinentia pigmenti would appear to support this mechanism as a potential route through which brain damage occurs and neurological symptoms can arise, as it’s caused by mutations that stop NEMO from functioning properly. Its symptoms include encephalopathy, stroke, and seizures constituting a similar disease profile to COVID-19’s associated neurological complications. In mice, the loss of NEMO’s function results in patchy hypoxia and the blood-brain barrier becoming leaky, potentially mirroring the way in which SARS-CoV-2 brings about these symptoms in COVID-19 patients.

As Mpro appears to be the main instigator here, the researchers posit that inhibitors of Mpro may be able to prevent the neurological complications of COVID-19. Another option centers around the deletion of Ripk3 in disease progression, which could be aided by RIPK1 inhibitors that have already entered clinical testing. If successful, the study authors suggest the treatments could be used for patients affected by SARS-CoV-2 and incontinentia pigmenti alike, making them a worthy avenue for further investigation.