Determine the role of antibodies and innate immune responses in the pathogenesis of neurologic post-acute sequelae of SARS-CoV2 (neuroPASC).

Compared to individuals who did not develop neurological complications following infection (n=94), those with neuroPASC (n=18) showed lower systemic antibody responses against SARS-CoV-2, including antibody-dependent complement deposition (ADCD), NK cell activation (ADNKA) and Fcg receptor binding. No differences in the antibody responses to EBV, Flu or HSV1 were observed. However, surprisingly, NeuroPASC showed expanded antibody responses to other common Coronaviruses, suggesting an original antigenic sin, where pre-existing immune responses against related viruses shape the response to current infection. Also, in neuroPASC, all antibody isotypes/subclasses were detected in the serum, whereas CSF was characterized by IgG1 (and absence of IgM), suggesting compartmentalized humoral responses within the CSF through selective transfer of antibodies from the serum to the CSF across the blood-brain-barrier, rather than intrathecal synthesis. Finally, CSF SARS-CoV-2 responses were selectively elevated in individuals with good outcome, whereas systemic responses against other common Coronaviruses were enriched in individuals with bad outcome.