Systems Biology of Newly-Infected RECOVER Participants

Introduction: This study will use a unique cohort that is only available through RECOVER. We are focusing efforts on healthy RECOVER participants who had not yet been infected with SARS-CoV-2, then were infected following enrollment. We will characterize autoantibodies and IgG responses using PhIP-seq, custom protein arrays, B cell repertoire analysis, and other proteomics methods. We will compare those participants who developed Long COVID (~10%) with those who did not develop Long COVID and fully recovered (~90%).

Objective: The overall objectives of this study are to identify new-onset autoantibodies in patients who are newly infected with SARS-CoV-2, and to identify antibodies and B cells that differentiate between patients with and without Long COVID.

Methods: There are 2 specific aims of this study. Aim 1 is to characterize autoantibodies (AAbs) in newly-infected RECOVER participants. We will test the hypothesis that transient AAbs develop following SARS-CoV-2 infection and that these will be more common in participants who develop Long COVID. We further hypothesize that some AAbs will cross-react with epitopes found in coronavirus proteins. We will use custom protein arrays (Stanford) to characterize antibodies against herpesviruses and self proteins. Comprehensive epitope mapping will be performed using PhIP-seq (UCSF). Aim 2 will characterize the B cell repertoire in serial samples from Long COVID patients: before infection baseline, at time of SARS-CoV-2 infection, and following development of Long COVID. We will test the hypothesis that autoreactive B cell frequencies will increase substantially, and that Epstein Barr Virus (EBV) infects a subset of autoreactive B cells in Long COVID. We further hypothesize that recombinant monoclonal antibodies (rMAbs) generated from Long COVID blood plasmablasts and EBV+ B cells will recognize EBV cross-reactive autoantigens. This will be performed by isolating single B cells, cloning paired heavy and light chain genes, and correlating with transcript profiles in individual cells. Results from all assays will be integrated and further correlated with clinical subphenotypes of Long COVID, and datasets generated in the Systems Biology study that is ongoing through TOPMed.

Results: Pending.

Conclusion/Discussion: Pending.

Key Topics:

• Assay and in vitro studies to gain mechanistic insights
• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Chronic immune dysfunction
• Clinical manifestations of chronic viral infections, biological pathways, immune-autoimmune disorders, systems, organs, or diseases,Collaborative and systems biology approaches
• Long COVID and other chronic conditions
• Studies of vascular injury, thrombosis, and other potential mechanisms of Long COVID
• Validation of published studies on potential mechanisms of Long COVID using data and biospecimens from RECOVER cohorts