TGF-β SIGNALING PATHWAY SHAPES ADAPTIVE IMMUNITY in EARLY SARS-CoV-2 INFECTION
Topics in Antiviral Medicine
; 30(1 SUPPL):116-117, 2022.
Article
in English
| EMBASE | ID: covidwho-1881009
ABSTRACT
Background:
SARS-CoV-2 induces cytokine response dysregulation and immune dysfunction. What remains unclear is how cytokine signaling shapes immune responses during early SARS-CoV-2 infection when adaptive immunity is developing. Our goal is to identify immune pathways that shape the early development of adaptive immune responses in COVID-19 patients. We performed paired single-cell transcriptomic and epigenomic profiling at two time-points of early SARS-CoV-2 infection to determine immune signatures of acute infection and epigenetic drivers that underpin immune response dynamics.Methods:
PBMC samples were collected from four moderate to severe COVID-19 patients at two early time-points (n = 3 for Week 1 and n = 3 for Week 2 after symptom onset, including 2 participants having paired blood sampling at both time points) and from two healthy controls (n = 2). Using paired scRNA-Seq and scATAC-Seq, we captured transcriptomic and epigenomic profiles in the same single cells to identify chromatin accessibility changes as a potential mechanism for the surge and decline of immune responses elicited during acute SARS-CoV-2 infection. Using bioinformatic approaches, we identified heterogeneous immune cell populations, modeled cell differentiation trajectories, determined dysregulated immune pathways through gene set enrichment analysis, and connected chromatin co-accessible landscapes.Results:
We captured transcriptomic and epigenomic profiles of 43,726 single cells and identified paired transcriptional and epigenetic landscapes in six major immune cell types CD4+ T cells, CD8+ T cells, B cells, dendritic cells, monocytes, and NK cells. We found that early SARS-CoV-2 infection induced a surge in IL-2, IL-6, IFN-α, IFN-γ, TNF-α, and NF-κB responses at Week 1 that declined at Week 2 in adaptive immune cells (CD4+ T, CD8+ T, and B cells). In contrast, TGF-β responses surged early at Week 1 and continued to increase at Week 2 in these cells. In B cells and plasmablasts, we found early surges of IGHA1 (encoding IgA heavy chain) and SOX4 (an essential transcription factor for B cell development) expressions that correlated with expression of SMAD-dependent TGF-β signaling pathway. Further, we found a notable increase in chromatin accessibility at the SMAD binding regulatory element 150 kb upstream of SOX4 in B cells of infected patients.Conclusion:
Our data suggest a significant increase in TGF-β activity that instructs dynamic B cell-associated protective immunity during early SARS-CoV-2 infection.
alpha interferon; CD4 antigen; endogenous compound; gamma interferon; immunoglobulin A; immunoglobulin enhancer binding protein; interleukin 2; interleukin 6; Smad protein; transcription factor; transcription factor Sox4; transforming growth factor beta; tumor necrosis factor; adaptive immunity; adult; B lymphocyte; blood sampling; CD4+ T lymphocyte; CD8+ T lymphocyte; cell differentiation; cell maturation; cell population; chromatin; clinical article; conference abstract; controlled study; coronavirus disease 2019; dendritic cell; epigenetics; female; gene expression; gene set enrichment analysis; genetic transcription; heavy chain; human; human cell; human tissue; immune response; immunocompetent cell; male; monocyte; natural killer cell; peripheral blood mononuclear cell; plasmablast; protein expression; protein fingerprinting; signal transduction; single cell RNA seq; T lymphocyte; TGF beta signaling
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Collection:
Databases of international organizations
Database:
EMBASE
Language:
English
Journal:
Topics in Antiviral Medicine
Year:
2022
Document Type:
Article
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