Virus World

Growing evidence links COVID-19 with acute and long-term neurological dysfunction. However, the pathophysiological mechanisms resulting in central nervous system involvement remain unclear, posing both diagnostic and therapeutic challenges. Here we show outcomes of a cross-sectional clinical study (NCT04472013) including clinical and imaging data and corresponding multidimensional characterization of immune mediators in the cerebrospinal fluid (CSF) and plasma of patients belonging to different Neuro-COVID severity classes. The most prominent signs of severe Neuro-COVID are blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. COVID-19 patients show decreased regional brain volumes associating with specific CSF parameters, however, COVID-19 patients characterized by plasma cytokine storm are presenting with a non-inflammatory CSF profile. Post-acute COVID-19 syndrome strongly associates with a distinctive set of CSF and plasma mediators. Collectively, we identify several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection. Both acute and chronic COVID-19 disease (also known as long-COVID) may affect the central nervous system. Here authors characterize the immunological profile of peripheral blood and cerebrospinal fluid of COVID-19 patients in order to identify the main factors that contribute to neurological impairment and the severity of neurological symptoms in Sars-CoV-2 infection.

Published in Nature Communications (Nov. 09, 2022):

https://doi.org/10.1038/s41467-022-34068-0 

For three months, Chelsea Alionar has struggled with fevers, headaches, dizziness and a brain fog so intense it feels like early dementia. She came down with the worst headache of her life on March 9, then lost her sense of taste and smell. She eventually tested positive for the coronavirus. But her symptoms have been stranger, and lasted longer, than most. “I tell the same stories repeatedly; I forget words I know,” she told me. Her fingers and toes have been numb, her vision blurry and her fatigue severe. The 37-year-old is a one of the more than 4,000 members of a Facebook support group for Covid survivors who have been ill for more than 80 days.

The more we learn about the coronavirus, the more we realize it’s not just a respiratory infection. The virus can ravage many of the body’s major organ systems, including the brain and central nervous system. Among patients hospitalized for Covid-19 in Wuhan, China, more than a third experienced nervous system symptoms, including seizures and impaired consciousness. Earlier this month, French researchers reported that 84 percent of Covid patients who had been admitted to the I.C.U. experienced neurological problems, and that 33 percent continued to act confused and disoriented when they were discharged.

According to Dr. Mady Hornig, a psychiatrist and epidemiologist at the Columbia University Mailman School of Public Health, the possibility that neurological issues “will persist and create disability, or difficulties, for individuals downstream is really looking more and more likely.” Infections have long been implicated in neurological diseases. Syphilis and H.I.V. can induce dementia. Zika is known to invade developing brains and limit their growth, while untreated Lyme disease can cause nerve pain, facial palsy and spinal cord inflammation. One man with SARS developed delirium that progressed into coma, and was found to have the virus in his brain tissue after his death.

Like a key, SARS-CoV-2—the virus that causes coronavirus disease 2019 (COVID-19) - attaches to specific molecules on the host cell surface, opening gateways into the cell interior. Viral entry into host cells triggers a prodigious immune response. Much of this battle is waged within the lungs, which explains why many patients hospitalized with COVID-19 have severe respiratory symptoms. Respiratory symptoms, however, are only part of the story. Increasing evidence points toward blood vessel inflammation as having a crucial impact on the severity of COVID-19. In addition, anywhere from 30 to 80 percent of patients experience neurological symptoms, including dizziness, headache, nausea, and loss of concentration. These symptoms suggest that SARS-CoV-2 also affects cells of the central nervous system. While there is no evidence yet that the virus invades the brain, new work by scientists at the Lewis Katz School of Medicine at Temple University shows that the spike proteins that extrude from SARS-CoV-2 promote inflammatory responses on the endothelial cells that form the blood-brain barrier. The study, published in the December print issue of the journal Neurobiology of Disease, is the first to show that SARS-CoV-2 spike proteins can cause this barrier to become "leaky," potentially disrupting the delicate neural networks within the brain.

"Previous studies have shown that SARS-CoV-2 infects host cells by using its spike proteins to bind to the angiotensin converting enzyme 2 (ACE2) on the host cell surface," explained Servio H. Ramirez, Ph.D., Professor of Pathology and Laboratory Medicine at the Lewis Katz School of Medicine at Temple University and principal investigator on the new study. ACE2 is expressed on endothelial cells, which form the inner lining of blood vessels, and serves a central role in mediating different functions of the cardiovascular system. According to Dr. Ramirez, "since ACE2 is a major binding target for SARS-CoV-2 in the lungs and vasculature of other organs in the body, tissues that are behind the vasculature, that receive blood from affected vessels, are at risk of damage from the virus." It has been unclear, however, whether ACE2 is also present in the brain vasculature or whether its expression changes in health conditions that worsen COVID-19, such as high blood pressure (hypertension). To find out, the team began by examining postmortem human brain tissue for vascular ACE2 expression, using tissues from individuals without underlying health conditions and from individuals in whom hypertension and dementia had been established. Analyses showed that ACE2 is in fact expressed throughout blood vessels in the frontal cortex of the brain and is significantly increased in the brain vasculature of persons with a history of hypertension or dementia.

The researchers then investigated the effects of the SARS-CoV-2 spike protein on brain endothelial cells in cell culture models. Introduction of the spike protein, particularly a portion designated subunit 1, produced substantial changes in endothelial barrier function that led to declines in barrier integrity. The researchers also uncovered evidence that subunit 2 of the SARS-CoV-2 spike protein can directly impact blood-brain barrier function. "This is of importance because unlike subunit 1, subunit 2 of the spike protein doesn't bind to ACE2, meaning that a breach to the blood-brain barrier could occur in a manner that is independent of ACE2," explained postdoctoral fellow and first author on the new report Tetyana P. Buzhdygan, Ph.D. Dr. Ramirez's team further investigated the effects of SARS-CoV-2 spike proteins on tissue-engineered microfluidic constructs designed to mimic a human brain capillary. "The tissue-engineered microfluidic models allow recapitulation of the 3-D cyto-architecture and mechanical forces caused by fluid movement, which the vasculature is continuously exposed to," said Allison M. Andrews, Ph.D., Assistant Professor in the Department of Pathology & Laboratory Medicine at LKSOM and a co-author on the report. Experiments showed that binding of spike protein subunit 1 increased barrier permeability in the engineered vessel-like constructs. "Our findings support the implication that SARS-CoV-2, or its shed spike proteins circulating in the blood stream, could cause destabilization of the blood-brain barrier in key brain regions," Dr. Ramirez said. "Altered function of this barrier, which normally keeps harmful agents out of the brain, greatly increases the possibility of neuroinvasion by this pathogen, offering an explanation for the neurological manifestations experienced by COVID-19 patients."...

Original study published in Neurobiology of Disease:

https://doi.org/10.1016/j.nbd.2020.105131