ABSTRACT
The oral mucosa remains an understudied barrier tissue. This is a site of rich exposure to antigens and commensals, and a tissue susceptible to one of the most prevalent human inflammatory diseases, periodontitis. To aid in understanding tissue-specific pathophysiology, we compile a single-cell transcriptome atlas of human oral mucosa in healthy individuals and patients with periodontitis. We uncover the complex cellular landscape of oral mucosal tissues and identify epithelial and stromal cell populations with inflammatory signatures that promote antimicrobial defenses and neutrophil recruitment. Our findings link exaggerated stromal cell responsiveness with enhanced neutrophil and leukocyte infiltration in periodontitis. Our work provides a resource characterizing the role of tissue stroma in regulating mucosal tissue homeostasis and disease pathogenesis.
Subject(s)
Immunity, Mucosal , Mouth Mucosa/cytology , Mouth Mucosa/immunology , Neutrophils/cytology , Adult , Epithelial Cells/cytology , Gene Expression Regulation , Genetic Predisposition to Disease , Gingiva/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Microbiota , Myeloid Cells/cytology , Periodontitis/genetics , Periodontitis/immunology , Periodontitis/pathology , Single-Cell Analysis , Stromal Cells/cytology , T-Lymphocytes/cytologyABSTRACT
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is an emerging respiratory pathogen that has rapidly spread in human populations. Severe forms of infection associate cytokine release syndrome and acute lung injury due to hyperinflammatory responses even though virus clearance is achieved. Key components of inflammation include immune cell recruitment in infected tissues, a step which is under the control of endothelial cells. Here, we review endothelial cell responses in inflammation and infection due to SARS-CoV-2 together with phenotypic and functional alterations of monocytes, T and B lymphocytes with which they interact. We surmise that endothelial cells function as an integrative and active platform for the various cells recruited, where fine tuning of immune responses takes place and which provides opportunities for therapeutic intervention.
Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , COVID-19/pathology , Endothelial Cells/pathology , Myeloid Cells/immunology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokines/immunology , Humans , Immunologic Memory , Myeloid Cells/cytology , T-Lymphocytes/cytology , T-Lymphocytes/immunologyABSTRACT
Coronavirus disease 2019 (COVID-19) manifests with a range of severities, but immune signatures of mild and severe disease are still not fully understood. Here, we use mass cytometry and targeted proteomics to profile the innate immune response of patients with mild or severe COVID-19 and of healthy individuals. Sampling at different stages allows us to reconstruct a pseudo-temporal trajectory of the innate response. A surge of CD169+ monocytes associated with an IFN-γ+MCP-2+ signature rapidly follows symptom onset. At later stages, we observe a persistent inflammatory phenotype in patients with severe disease, dominated by high CCL3 and CCL4 abundance correlating with the re-appearance of CD16+ monocytes, whereas the response of mild COVID-19 patients normalizes. Our data provide insights into the dynamic nature of inflammatory responses in COVID-19 patients and identify sustained innate immune responses as a likely mechanism in severe patients, thus supporting the investigation of targeted interventions in severe COVID-19.
Subject(s)
COVID-19/immunology , Immunity, Innate , Adult , C-Reactive Protein/analysis , COVID-19/pathology , COVID-19/virology , Cytokines/blood , Female , Humans , Male , Mass Spectrometry , Middle Aged , Monocytes/cytology , Monocytes/metabolism , Myeloid Cells/cytology , Myeloid Cells/metabolism , Proteomics/methods , SARS-CoV-2/isolation & purification , Severity of Illness Index , Sialic Acid Binding Ig-like Lectin 1/metabolismABSTRACT
Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.