Distinct Effector B cell and Autoantibody Responses Contribute to Long COVID Pathogenesis

Abstract

The disease COVID-19 due to the coronavirus SARS-CoV-2 has resulted in over 770 million confirmed cases worldwide with 1% death rate as in August 2023. 20%–31% of symptomatic patients require hospitalization, with intensive care unit (ICU) admission rates ranging from 4.9%– 11.5%, and fatality rates ranging from 2%–10%. Patients with more severe COVID-19 infections are distinguished by significant immune dysregulation, the nature of which is incompletely understood. Moreover, around 31%–69% of COVID-19 patients suffer from post-acute sequelae of COVID-19 (PASC), or long COVID, which is defined as a range of new, returning, or ongoing health problems people can experience four or more weeks following initial SARS-CoV-2 infection. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. To address the knowledge gaps in both acute and long COVID-19, we performed a longitudinal multi-omic analysis of 309 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis to convalescence at 2-3 months. We identified unique immune subsets and plasma factors associated with acute COVID and long COVID and provided a mechanistic view of a unique B cell subset that may contribute to pathogenicity of long COVID, using integrated single-cell multiomics from peripheral immune cells, plasma omics, functional measurements, and clinical observations. We begin with a comprehensive analysis of samples from acute COVID-19 infections (Chapter 1). We then explored how tocilizumab, an anti-IL-6 receptor drug, perturbed the immune landscapes in acute COVID (Chapter 2). We further used the multiomics approach to study biological factors that are associated with long COVID (Chapter 3). Finally, we performed a deep analysis exploring the joint single-cell spaces of transcriptome and genome-wise chromatin accessibility to understand the regulatory elements that drive the differentiation of a B cell subset which gave rise to autoantibodies and thus likely contribute to pathogenesis of long COVID (Chapter 4). At last, we summarized our key findings in Chapter 5.