Viral and Immune-Mediated CNS Pathology During SARS-CoV-2 Infection

Introduction: The focus of this study was to identify autoantibodies and other inflammatory signatures associated with neuro-PASC from analyzing patient sera, identify biomarkers of neuro-PASC through machine learning, and investigate the causal link between AAB and neurologic disease by developing two complementary mouse models of neuro-PASC.

Objective: To identify the role of autoantibodies in neurological pathologies in Long COVID.

Methods: We have collated ~500 post-acute sequelae of SARS-CoV-2 (PASC) patient plasma and sera samples from 4 separate, multisite cohorts to identify AABs that correlate with neuro-PASC (Aim 1.1), study longitudinal AAB responses in a well-defined cohort of patients with or without neuro-PASC for which we have extensive data from their acute SARS-CoV-2 infection (Aim 1.2) and to use machine learning approaches to identify biomarkers of neuro-PASC (Aim 1.3). We coupled clinical analysis with mouse models to address, 1) how AAB that correlate with neurological symptoms in patients contribute to neurological symptoms of PASC through development of an AAB-transfer mouse model for neuro-PASC (Aim 2.1), and 2) probe how SARS-CoV-2 infection synergizes with host genetic predispositions towards autoimmunity to develop AAB that lead to neuro-PASC (Aim 2.2). The proposed research is hypothesis-driven, innovative, highly interdisciplinary, and has a strong potential to inform the diagnosis, prevention, mitigation, and treatment of PASC through elucidating the pathogenesis of post-acute sequelae and the identification of associated mechanistic pathways.

Results: Our work has demonstrated that a significantly elevated number of autoantibodies is found in people with Long COVID. These antibodies target the CNS and PNS, and passive transfer of purified IgG leads to recapitulation of patient-reported symptoms, including pain, disorientation, dizziness, and headache. Our work is currently under review for publication. The preprinted version is titled "A causal link between autoantibodies and neurological symptoms in long COVID."

Conclusion/Discussion: Our work identified a subset of patients with Long COVID with pathological autoantibodies. These patients might benefit from B cell depleting therapies and FcRn inhibitors.

Key Topics:

• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Chronic immune dysfunction
• Collaborative and systems biology approaches
• Developing models of similar diseases/syndrome