FLARE-LC: Functional Autoantibodies Linking Autonomic Regulation and Effects of Long Covid

Introduction: Individuals with Long COVID (LC) often have autoantibodies to ion channels and cell surface receptors, including G-protein coupled receptors (GPCRs). However, clear links between specific GPCR autoantibodies and LC symptoms, including pain and autonomic nervous system dysfunction, remain to be established.

Objective: This study tests the hypothesis that patients with LC have functionally active autoantibodies to GPCRs found in sympathetic neurons, sensory neurons, and cardiomyocytes, and that these Aabs are differentially associated with specific LC symptom clusters.

Methods: We will examine serum samples from 900 participants in the RECOVER Adult Cohort tested at 1 year after the initial COVID diagnosis: 600 with Long COVID Index (LCI) > 11, 150 LCI 1-10, and 150 LCI 0. Samples will undergo a blinded high-throughput screen for intracellular calcium elevation as a reporter of neuronal excitation in rat dorsal root ganglion, trigeminal, and sympathetic neurons, and separate screens for spontaneous beating rate and calcium currents in human iPSC-derived cardiomyocytes. A subset of positive responding samples will be tested with patch-clamp recording or calcium imaging in peripheral neurons for detailed characterization of pharmacology and physiology, and by ELISA for GPCR binding. AI/machine learning (AI/ML) approaches will be used to relate cellular responses to detailed survey and demographic data in the selected participants, and to identify new symptom clusters across the entire cohort. A publicly available data visualization dashboard will allow comparison of project responses and other RECOVER studies or separately published data sets.

Results: Pending.

Conclusion/Discussion: These studies will link functional autoantibody responses against GPCRs expressed in peripheral neurons and cardiomyocytes to pain and autonomic dysfunction, two of the most common and disabling symptoms of Long COVID. Results may allow identification of symptom-specific biomarkers and potential therapeutic targets.

Key Topics:

• Assay and in vitro studies to gain mechanistic insights
• Chronic immune dysfunction
• Collaborative and systems biology approaches
• Validation of published studies on potential mechanisms of Long COVID using data and biospecimens from RECOVER cohorts