BREAKING! MIT Study Finds That NeuroCOVID Manifestations In Post Infections Are Determined By Immunologic Imprinting From Previous Coronaviruses!
: A new study lead by researchers from Ragon Institute of MGH, MIT and Harvard Medical School, Cambridge – USA has found that NeuroCOVID manifestations in post infections are determined by immunologic imprinting from previous coronaviruses!
The study also involved medical researchers from the Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona- Italy and the Department of Neurology/Stroke Unit, San Maurizio hospital, Bolzano -Italy.
The COVID-19 disease which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health emergency. Although SARS-CoV-2 is primarily a respiratory pathogen, extra-respiratory organs, including the central nervous system (CNS), can also be affected.
Various neurologic symptoms have been observed not only during acute SARS-CoV-2 infection, but also at distance from respiratory disease, also known as long-COVID or neurological post-acute sequelae of COVID-19 (neuroPASC).
The detailed pathogenesis of neuroPASC is not well understood, but hypotheses include SARS-CoV-2-induced immune dysfunctions, hormonal dysregulations, and persistence of SARS-CoV-2 reservoirs.
The study team utilized a high throughput systems serology approach to dissect the humoral response to SARS-CoV-2 (and other common Coronaviruses - 229E, HKU1, NL63, OC43) in the serum and cerebrospinal fluid (CSF) from 112 infected individuals who developed or did not develop neuroPASC.
The study findings surprisingly showed unique SARS-CoV-2 humoral profiles in the CSF of neuroPASC.
Interestingly, all antibody isotypes (IgA, IgM, IgA) and subclasses (IgA1-2; IgG1-4) were detected in serum, whereas CSF was characterized by focused IgG1 (and absence of IgM).
The study findings argue in favor of compartmentalized brain-specific responses against SARS-CoV-2 through selective transfer of antibodies from the serum to the CSF across the blood-brain-barrier, rather than intrathecal synthesis, where more diversity in antibody classes/subclasses would be expected.
Also, compared to individuals who did not develop post-acute neurological complications following infection (n=94), those with neuroPASC (n=18) exhibited attenuated systemic antibody responses against SARS-CoV-2, characterized by decreased capacity to activate antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and to bind Fcγ receptors.
Shockingly however, neuroPASC showed significantly expanded antibody responses to other common Coronaviruses, including 229E, HKU1, NL63, and OC43.
This biased humoral activation across coronaviruses was particularly enriched in neuroPASC individuals with poor outcome, suggesting an original antigenic sin (or immunologic imprinting), where pre-existing immune responses against related viruses shape the response to current infection, as a key prognostic marker of neuroPASC disease.
The study findings point to a pathogenic role for compromised anti-SARS-CoV-2 responses in the CSF, likely resulting in incomplete virus clearance from the brain and persistent neuroinflammation, in the development of post-acute neurologic complications of SARS-CoV-2 infection.
The study findings were published on a preprin
t server and are currently being peer reviewed.
The study findings clearly point to a pathogenic role for compromised anti-SARS-CoV-2 responses in cerebrospinal fluid.
The study team are the first to use a high throughput systems serology method to compare serum and cerebrospinal fluid (CSF) samples from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected individuals with and without long coronavirus disease (COVID) symptoms to determine changes in the SARS-CoV-2 humoral immune responses.
It should be noted that one of the emerging long-term impacts of SARS-CoV-2 infections are persistent complications in organ systems other than the respiratory system, such as the nervous system.
The neurological post-acute sequelae of COVID-19 (neuroPASC) include impaired cognitive function, difficulty concentrating, persistent headaches and confusion, strokes and even encephalitis, experienced for several months after recovering from a SARS-CoV-2 infection.
Past research covered in various COVID-19 News
coverages have hypothesized various pathophysiological mechanisms to explain the symptoms of neuroPASC, including the presence of viral reservoirs, immune dysfunctions, hormone dysregulation, vagus nerve signal impairment, and resurgence of neurotrophic infections.
Considering the role of antibodies in local pathology and as biomarkers of pathogen exposure, humoral signatures can be used to understand the mechanisms behind the neurological symptoms of long-COVID.
For the study, the research team recruited individuals who had SARS-CoV-2 infections during the first COVID-19 wave in Italy between March and August 2020, with and without post-acute neurological complications after COVID-19.
In the research, the inclusion criteria for individuals in the neuroPASC group comprised neurological manifestations or changes in neurological status that any other cause could not explain and a SARS-CoV-2 infection confirmed by a positive polymerase chain reaction (PCR) test or positive SARS-CoV-2 immunoglobulin G (IgG) serology, with or without COVID-19 symptoms.
Doctors, nurses and other healthcare professionals who were routinely tested as a part of SARS-CoV-2 surveillance and who had positive PCR tests for SARS-CoV-2 infections but no neuroPASC manifestations were selected for the control group.
It was noted that none of the patients were vaccinated when the study was conducted, and SARS-CoV-2 infections were confirmed at the onset of the study using enzyme-linked immunosorbent assay (ELISA) for positive SARS-CoV-2 IgG.
For the study, serum samples were obtained from all the patients, and CSF was obtained from the neuroPASC patients only if a diagnostic assessment was required. Neurological outcomes were assessed on a modified Rankin Scale (mRS), with mRS values less than two indicating good outcomes and greater than two indicating poor outcomes.
All antibody responses were measured against five SARS-CoV-2 antigens, including the spike protein, receptor binding domain (RBD), subunits S1 and S1, and the nucleocapsid protein. Antibody responses against four other coronaviruses and three non-coronavirus control antigens were also measured.
Also, isotype levels, Fc receptor binding, and antibody subclasses specific to the antigens were determined.
The study team additionally also determined antibody-dependent cellular and neutrophil phagocytosis and antibody-dependent complement deposition and performed ELISA to measure the antibody-dependent natural killer cell activation.
Interestingly, the study findings revealed unique humoral profiles in patients that exhibited neuroPASC. The serum samples of neuroPASC patients contained all antibody isotypes and subclasses, but the CSF contained focused IgG1 and lacked IgM.
Such humoral profiles indicated that anti- SARS-CoV-2 responses
underwent brain-specific compartmentalization, with selected antibodies being transferred from the serum to the CSF across the blood-brain barrier instead of being synthesized intrathecally which would result in increased antibody diversity in the CSF.
It was also found that patients who developed neuroPASC after SARS-CoV-2 infections also exhibited decreased activation of antibody-dependent complement deposition and antibody-dependent natural killer cells and lower Fcγ receptor binding.
Importantly, NeuroPASC patients, especially those who showed poor outcomes (mRS greater than two), also displayed antibody responses to other coronaviruses, including human coronavirus (HCoV)- NetherLand 63 (NL63), HCoV- Hong Kong University 1 (HKU1), HCoV- Organ Culture 43 (OC43), and HCoV-229E.
Significantly, the humoral activation against other HCoVs suggested that immunologic imprinting, where current immune responses are shaped by pre-existing immunity to related viruses, could be a neuroPASC prognostic marker.
The study findings also indicated the role of improper viral clearance from the brain and neuroinflammation due to a compromised CSF immune response to SARS-CoV-2 in the development of neurological complications during long COVID.
The study findings suggested different humoral signatures in the serum and CSF of neuroPASC patients, accompanied by diminished responses to SARS-CoV-2 but expanded responses to other human coronaviruses, indicating immunologic imprinting.
The study team believes that the neurological manifestations of long COVID could be due to incomplete clearance of the virus from the brain causing neuroinflammation and that immunologic imprinting could be a prognostic marker for neuroPASC.
The study team commented, “The study findings suggest a previously unappreciated role for immunologic imprinting from other Coronaviruses that may induce a defective antibody-mediated control of SARS-CoV-2 infection, resulting in incomplete or delayed virus clearance, and persistence of systemic immune activation and neuroinflammation involved in the pathogenesis of neuroPASC. Whether the markers identified here are simply biomarkers or mechanistic players in neuroPASC remains unknown, but may support the more effective identification, management, and potential treatment of individuals suffering from neuroPASC.”
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