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Study points to a pathogenic role for compromised anti-SARS-CoV-2 responses in cerebrospinal fluid

In a recent study posted to the medRxiv* preprint server, a team of researchers used 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.

Study: Neurologic sequalae of COVID-19 are determined by immunologic imprinting from previous Coronaviruses. Image Credit: Casa nayafana/Shutterstock


One of the emerging long-term impacts of the coronavirus disease 2019 (COVID-19) pandemic is 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, and even encephalitis, experienced for several months after recovering from a SARS-CoV-2 infection.

Studies 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. Given 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.

About the study

In the present study, 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, were recruited.

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.

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. 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.

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.

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.

Isotype levels, Fc receptor binding, and antibody subclasses specific to the antigens were determined. In addition, the team 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.


The results 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. These 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.

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.

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. 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.

Cumulatively, the results 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.


Overall, the results 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 authors believe 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.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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