Viral and immune-mediated CNS pathology during SARS-CoV-2 infection

Supplement Project Summary Since its appearance in late 2019, SARS-CoV-2 has spread globally and resulted in 5.5 million deaths in 24 months. Our group's published work has demonstrated that the pathogenesis of COVID-19 is characterized by overlapping TH1, TH2, and TH17 responses and the presence of diverse, disease-modifying autoantibodies (AAB). The extent of recovery following acute SARS-CoV-2 infection is varied, with 14-35% of patients reporting persistent or new symptoms during convalescence, collectively termed as post-acute sequelae of COVID-19 (PASC or "Long COVID"). While PASC affects multiple organs, a prominent feature of PASC includes neurological symptoms including unremitting fatigue, myalgia, insomnia, mental slowing, and confusion ('Neuro- PASC'). Although persistent symptoms are common following other severe viral infections, PASC patients demonstrate significant and unique elevations in sequelae even when matched against comparator groups. In the parent R01 proposal, we outlined our goals to investigate the encephalitic potential of SARS-CoV-2 (Aim 1), to evaluate effects of CNS, respiratory and combination SARS-CoV-2 infection on disease outcomes in mouse models (Aim 2), and to determine the CNS responses in COVID-19 patients with neurological symptoms (Aim 3). The supplement extends these studies to investigation of post-acute neurologic sequelae of COVID. To this end, we have collated ~500 PASC patient plasma and sera samples from 4 separate, multisite cohorts to identify AABs that correlate with neuro-PASC (Suppl. 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 COVID infection (Suppl. Aim 1.2) and to use machine learning approaches to identify biomarkers of neuro-PASC (Suppl. Aim 1.3). In addition, while the original grant proposal uses SARS-CoV-2 infection to model neurological diseases as a result of direct virus infection in mice, this supplement takes an orthogonal approach to understand 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 (Suppl. 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 (Suppl. 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.