SARS-CoV-2 Spike Proteins Disrupt the Blood-Brain Barrier
Between 30 and 80 percent of COVID-19 patients experience neurological symptoms, such as memory loss, headaches, difficulty balancing, nausea, or issues concentrating, better known as the ‘COVID-19 fog.’ This phenomenon suggests SARS-CoV-2 affects parts of the central nervous system, not just the respiratory and cardiovascular systems.
Mild cases of COVID-19 in patients as young as 30-years-old can lead to this COVID-19 fog, and some SARS-CoV-2 survivors continue to experience cognitive and psychiatric issues even after recovery. COVID-19 patients “forget the names of people they know well, they can’t follow along during business conversations, prioritizing and planning is suddenly difficult, they are inexplicably anxious and sleep poorly.” In that vein, patients experienced sensory issues: loss of smell or taste when infected with COVID-19 is common, but people have now reported changes in appetite, lightheadedness and dizziness, discomfort, and new intense headaches that often do not respond to traditional pain medication or methods of relief. The discovery of these neurological, behavioral, and sensory changes necessitates further research into the long-term effects of SARS-CoV-2 on the brain and its functions.
A new study by researchers at the Lewis Katz School of Medicine at Temple University suggests that spike proteins, viral membrane proteins that control cell entry, protruding from SARS-CoV-2 promote inflammatory responses on endothelial cells in the blood-brain barrier. Endothelial cells line blood vessels, form a permeable membrane, and regulate blood flow, and they are vital in wound healing, angiogenesis, inflammatory responses, maintaining the blood-brain barrier, and play a role in diabetes and cardiovascular diseases. SARS-CoV-2 spike proteins disrupt brain-blood barrier integrity and thus, endangers neural networks in the brain.
Servio H. Ramirez, Ph.D., Professor of Pathology and Laboratory Medicine at the Lewis Katz School of Medicine and principal investigator for this study, said: “Previous 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.” ACE2 is expressed on endothelial cells, which moderate different functions and processes in the cardiovascular system. It is a binding target for SARS-CoV-2 in the lungs and vasculature throughout the body, so organs and tissues that receive blood from damaged blood vessels can be damaged by the coronavirus, explaining the severe respiratory issues COVID-19 patients experience and the national need for ventilators.
Examining postmortem human brain tissue for vascular ACE2 expression (excluding individuals with hypertension, dementia, or other underlying health conditions) showed that ACE2 is expressed in blood vessels in the front cortex of the brain and overall brain vasculature.
In cell cultures examining the interplay of SARS-CoV-2 spike proteins and brain endothelial cells, subunit 1 of the spike protein reduced endothelial barrier integrity. Notably, subunit 2 does not bind to ACE2 but still directly alters the blood-brain barrier function.
Dr. Ramirez and the Lewis Katz School of Medicine team used tissue-engineered microfluidic models to simulate capillaries that appear in the human brain. Their research showed that the binding of spike protein subunit 1 increased endothelial barrier permeability. Thus, SARS-CoV-2 spike proteins that circulate in a patient’s bloodstream can destabilize the blood-brain barrier, opening the door for pathogens to enter the brain (neuroinvasion) and disrupt necessary brain functions. Longer-term effects of a disrupted blood-brain barrier function at the hands of SARS-CoV-2 are unknown and will require future study. What we know is that the brain vasculature is “extremely branched, so even a small amount of neuroinflammation can be very damaging,” said Dr. Tetyana P. Buzdhygan. Additionally, the presence of comorbid or pre-existing health conditions, which also damage brain vasculature, can be extremely detrimental to a patient’s neurology. Another question that remains unanswered is the extent of the SARS-CoV-2 spike protein’s neuroinvasion abilities, such as whether the coronavirus can enter neurons or glial cells that lie beyond the blood-brain barrier.
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Raghava Potula, Allison M. Andrews, Servio H. Ramirez et al. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Neurobiology of Disease, 2020; 146: 105131 DOI: 10.1016/j.nbd.2020.105131