Abstract
SARS-CoV-2 infection triggers profound and variable immune responses in human hosts. Chromatin remodeling has been observed in individuals severely ill or convalescing with COVID-19, but chromatin remodeling early in disease prior to anti-spike protein IgG seroconversion has not been defined. We performed the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) and RNA-seq on peripheral blood mononuclear cells (PBMCs) from outpatients with mild or moderate symptom severity at different stages of clinical illness. Early in the disease course prior to IgG seroconversion, modifications in chromatin accessibility associated with mild or moderate symptoms were already robust and included severity-associated changes in accessibility of genes in interleukin signaling, regulation of cell differentiation and cell morphology. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif accessibility for individual PBMC cell types over time. The most extensive remodeling occurred in CD14+ monocytes, where sub-populations with distinct chromatin accessibility profiles were observed prior to seroconversion. Mild symptom severity was marked by upregulation of classical antiviral pathways, including those regulating IRF1 and IRF7, whereas in moderate disease, these classical antiviral signals diminished, suggesting dysregulated and less effective responses. Together, these observations offer novel insight into the epigenome of early mild SARS-CoV-2 infection and suggest that detection of chromatin remodeling in early disease may offer promise for a new class of diagnostic tools for COVID-19.
【초록키워드】 COVID-19, Monocytes, Evolution, SARS-CoV-2, IgG, immune response, Antiviral, SARS-COV-2 infection, severity, Sequencing, Infection, diagnostic, Symptom, Peripheral blood, RNA-Seq, Accessibility, Seroconversion, interleukin, immune responses, Peripheral blood mononuclear cells, Mild, PBMC, morphology, outpatients, disease, moderate, IRF1, Signaling, Outpatient, PBMCs, Pathways, IRF7, Trigger, triggers, transcription factor, mononuclear cells, cell types, cell type, early disease, mononuclear cell, observation, Regulation, moderate symptom, Mild symptom, moderate disease, profile, individual, disease course, promise, Stage, single-cell analyses, hosts, upregulation, symptom severity, transposase, CD14, modifications, remodeling, Modification, mild SARS-CoV-2 infection, chromatin, motif, cell differentiation, offer, epigenome, CD14+ monocytes, anti-spike protein IgG, responses, effective, Cell, ATAC-seq, interleukin signaling, robust, Course, defined, classical, performed, occurred, the disease, less, changes in, dysregulated, single-cell analysis, with COVID-19, 【제목키워드】 mononuclear cell, COVID-19 disease severity,