Immune response triggered by COVID-19 may damage the brain
SARS-CoV-2 infection can trigger the production of immune molecules that damage cells lining blood vessels in the brain, causing platelets to stick together and form clots. Blood proteins also leak from the blood vessels, leading to inflammation and the destruction of neurons.
In a study published in Brain, researchers from the National Institute of Neurological Disorders and Stroke (NINDS) examined brain changes in nine people who died suddenly after contracting the virus.
The scientists found evidence that antibodies—proteins produced by the immune system in response to viruses and other invaders—are involved in an attack on the cells lining the brain’s blood vessels, leading to inflammation and damage. Consistent with an earlier study from the group, SARS-CoV-2 was not detected in the patients’ brains, suggesting the virus was not infecting the brain directly.
Understanding how SARS-CoV-2 can trigger brain damage may help inform development of therapies for COVID-19 patients who have lingering neurological symptoms.
“Patients often develop neurological complications with COVID-19, but the underlying pathophysiological process is not well understood,” said Avindra Nath, MD, Clinical Director at NINDS and the senior author of the study. “We had previously shown blood vessel damage and inflammation in patients’ brains at autopsy, but we didn’t understand the cause of the damage. I think we’ve gained important insight into the cascade of events.”
Dr. Nath and his team found that antibodies produced in response to COVID-19 may mistakenly target cells crucial to the blood-brain barrier. Tightly packed endothelial cells help form the blood-brain barrier, which keeps harmful substances from reaching the brain while allowing necessary substances to pass through. Damage to endothelial cells in blood vessels in the brain can lead to leakage of proteins from the blood. This causes bleeds and clots in some COVID-19 patients and can increase the risk of stroke.
For the first time, researchers observed deposits of immune complexes—molecules formed when antibodies bind antigens (foreign substances)—on the surface of endothelial cells in the brains of COVID-19 patients. Such immune complexes can damage tissue by triggering inflammation.
The study builds on their previous research, which found evidence of brain damage caused by thinning and leaky blood vessels. They suspected that the damage may have been due to the body’s natural inflammatory response to the virus.
To further explore this immune response, Dr. Nath and his team examined brain tissue from a subset of patients in the previous study. The nine individuals, age 24 to 73, were chosen because they showed signs of blood vessel damage in the brain based on structural brain scans. The samples were compared to those from 10 controls. The team looked at neuroinflammation and immune responses using immunohistochemistry, a technique that uses antibodies to identify specific marker proteins in the tissues.
As in their earlier study, researchers found signs of leaky blood vessels, based on the presence of blood proteins that normally do not cross the blood brain barrier. This suggests that the tight junctions between the endothelial cells in the blood brain barrier are damaged.
Dr. Nath and his colleagues found evidence that damage to endothelial cells was likely due to an immune response—discovering deposits of immune complexes on the surface of the cells.
These observations suggest an antibody-mediated attack that activates endothelial cells. When endothelial cells are activated, they express proteins called adhesion molecules that cause platelets to stick together. High levels of adhesion molecules were found in endothelial cells in the samples of brain tissue.
“Activation of the endothelial cells brings platelets that stick to the blood vessel walls, causing clots to form and leakage to occur. At the same time the tight junctions between the endothelial cells get disrupted causing them to leak,” Nath explained. “Once leakage occurs, immune cells such as macrophages may come to repair the damage, setting up inflammation. This, in turn, causes damage to neurons.”
Researchers found that in areas with damage to the endothelial cells, more than 300 genes showed decreased expression, while six genes were increased. These genes were associated with oxidative stress, DNA damage, and metabolic dysregulation. This may provide clues to the molecular basis of neurological symptoms related to COVID-19 and offer potential therapeutic targets.
Together, these findings give insight into the immune response damaging the brain after COVID-19 infection. But it remains unclear what antigen the immune response is targeting, as the virus itself was not detected in the brain. It is possible that antibodies against the SARS-CoV-2 spike protein could bind to the ACE2 receptor used by the virus to enter cells. More research is needed to explore this hypothesis.
The study may also have implications for understanding and treating long-term neurological symptoms after COVID-19, which include headache, fatigue, loss of taste and smell, sleep problems, and “brain fog.” Had the patients in the study survived, the researchers believe they would likely have developed Long COVID.
“It is quite possible that this same immune response persists in Long COVID patients resulting in neuronal injury,” said Nath. “There could be a small indolent immune response that is continuing, which means that immune-modulating therapies might help these patients. So, these findings have very important therapeutic implications.”
The results suggest that treatments designed to prevent the development of the immune complexes observed in the study could be potential therapies for post-COVID neurological symptoms.
Theranos whistleblowers and experts on artificial intelligence and genomic sequencing
AACC welcomed thousands of medical professionals and healthcare leaders to the 2022 AACC Annual Scientific Meeting & Clinical Lab Expo from July 24-28.
The meeting featured groundbreaking diagnostic advances that will solve challenging patient health problems, and affirmed just how essential laboratory medicine professionals are to patient safety and care.
As of Wednesday, July 27, nearly 17,000 laboratory medicine professionals had registered for the meeting—a clear sign that meeting attendance has bounced back to pre-pandemic levels. More attendees are expected today, the last day of the meeting.
A major highlight of the conference program was an in-depth discussion with Theranos whistleblowers Erika Cheung and Tyler Shultz about their efforts to reveal Theranos’ fraud and protect patients. The session offered a vivid lesson in the standards of ethics and accountability at work within the profession.
Attendees also had the chance to see five plenary talks presented by life sciences pioneers.
In the opening keynote, Dr. Lucila Ohno-Machado discussed performance measures that may help clinicians select precision medicine artificial intelligence models for routine use.
Monday’s plenary speaker, Dr. George Church—winner of AACC’s 2022 Wallace H. Coulter Lectureship Award—focused on combining machine learning with multiplexing and how this is the key to unlocking the treasure chest of genomic technologies.
In Tuesday’s plenary, Dr. Alysson Muotri explored brain organoids, which have been used to model the neurotropic effects of SARS-CoV-2 and provide insight into organogenesis and neurotoxicology.
On Wednesday, Dr. Thomas Lee described a three-component model for building trust between patients and the healthcare workforce.
In the closing keynote, Dr. Livia Schiavinato Eberlin presented on the development and application of direct mass spectrometry techniques used in clinical microbiology labs, clinical pathology labs, and the operating room.
As part of AACC’s Disruptive Technology Award competition, biotech innovators presented novel technologies that could help more patients get accurate diagnoses. Nanopath won with its solid-state biosensing platform, which provides clinically actionable genetic information in less than 15 minutes and could greatly improve routine women’s health screening at the point of care.
The 2022 AACC Clinical Lab Expo also featured 781 exhibitors and covered 246,700 net square feet. This dynamic exhibit featured cutting-edge tests from all laboratory medicine disciplines, including COVID-19 testing, artificial intelligence, mobile health, molecular diagnostics, mass spectrometry, point of care, and automation.
Attend the ASCP 2022 annual meeting
Registration is now open for the ASCP annual meeting taking place September 7-9 in Chicago and virtually.
Key takeaways are:
- Learn from and interact with leading experts
- Stay up-to-date and learn new skills
- Access more content with pre-meeting virtual sessions
- Find new vendors and suppliers
- Network and have fun with peers
Rule updates proficiency testing requirements for CLIA laboratories
The Centers for Medicare & Medicaid Services and Centers for Disease Control and Prevention published a final rule that would update 1992 proficiency testing and referral requirements under the Clinical Laboratory Improvement Amendments. Nearly 36,000 CLIA-certified laboratories, including hospital laboratories, are enrolled in CMS-approved proficiency testing programs. The final rule addresses and updates current analytes (that is, substances or constituents for which the laboratory conducts testing) and newer technologies. It also finalizes regulations to reflect those laboratories that perform moderate- and high-complexity testing and voluntarily participate in proficiency testing for waived tests (for example, simple tests, such as urine pregnancy tests) are subject to compliance. In the final rule, and a related Fact Sheet, CMS states that this will align the regulations with the CLIA statute, which does not exclude waived tests from the ban on improper proficiency testing referral. To view the final rule and related Fact Sheet, see:
www.govinfo.gov/content/pkg/FR-2022-07-11/pdf/2022-14513.pdf and www.cms.gov/files/document/clia-1988-proficiency-testing-regulations-related-analytes-and-acceptable-performance-cms-3355-f.pdf
