ABSTRACT
The cell-mediated protective and pathogenic immune responses to SARS-CoV-2 infection remain largely elusive. Here we identified 76 distinct cell subsets in the PBMC samples that were associated with various clinical presentations of COVID-19 using scRNA-seq technology coupled with a deep and comprehensive analysis of unique cell surface markers and differentially expressed genes. We revealed that (TRAV1-2+CD8+)MAIT cells and (NCAM1hiCD160+)NK cells significantly enriched in the asymptomatic subjects whereas (LAG3+CD160+CD8+)NKT cells increased in the symptomatic patients. We also observed that (CD68-CSF1R-IL1BhiCD14+)classical monocytes were positively correlated with the disease severity. Moreover, (CD33-HLA-DMA-CD14+)classical monocytes and (CLEC10A-S100A9lo)pDC were associated with the viral persistence. The GO and KEGG analyses identified enriched pathways related to immune responses, inflammation, and apoptosis. These findings may enhance our understanding of the immunopathogenesis of COVID-19 and help develop novel strategies against SARS-CoV-2 infection.
Subject(s)
COVID-19/diagnosis , COVID-19/immunology , Killer Cells, Natural/immunology , Monocytes/immunology , Mucosal-Associated Invariant T Cells/immunology , Natural Killer T-Cells/immunology , SARS-CoV-2/physiology , Asymptomatic Infections , Female , Flow Cytometry , Humans , Immunophenotyping , Male , Middle Aged , Severity of Illness Index , Viral LoadABSTRACT
Upon virus infection, CD8+ T cell accumulation is tightly controlled by simultaneous proliferation and apoptosis. However, it remains unclear how TCR signal coordinates these events to achieve expansion and effector cell differentiation. We found that T cell-specific deletion of nuclear helicase Dhx9 led to impaired CD8+ T cell survival, effector differentiation, and viral clearance. Mechanistically, Dhx9 acts as the key regulator to ensure LCK- and CD3ε-mediated ZAP70 phosphorylation and ERK activation to protect CD8+ T cells from apoptosis before proliferative burst. Dhx9 directly regulates Id2 transcription to control effector CD8+ T cell differentiation. The DSRM and OB_Fold domains are required for LCK binding and Id2 transcription, respectively. Dhx9 expression is predominantly increased in effector CD8+ T cells of COVID-19 patients. Therefore, we revealed a previously unknown regulatory mechanism that Dhx9 protects activated CD8+ T cells from apoptosis and ensures effector differentiation to promote antiviral immunity independent of nuclear sensor function.
Subject(s)
Antiviral Agents/pharmacology , Arenaviridae Infections/prevention & control , CD8-Positive T-Lymphocytes/immunology , COVID-19/prevention & control , DEAD-box RNA Helicases/metabolism , Immunity, Innate , Neoplasm Proteins/metabolism , Animals , Arenaviridae Infections/immunology , Arenaviridae Infections/metabolism , Arenaviridae Infections/pathology , COVID-19/immunology , COVID-19/metabolism , COVID-19/pathology , Cell Differentiation , DEAD-box RNA Helicases/genetics , Humans , Lymphocyte Activation , Lymphocytic choriomeningitis virus/physiology , Mice , Neoplasm Proteins/genetics , SARS-CoV-2/physiology , Virus ReplicationABSTRACT
A novel pneumonia-associated respiratory syndrome named coronavirus disease-2019 (COVID-19), which was caused by SARS-CoV-2ï¼broke out in Wuhan, China, in the end of 2019. Unfortunately, there is no specific antiviral agent or vaccine available to treat SARS-CoV-2 infections. The information regarding the immunological characteristics in COVID-19 patients remains limited. Here, we collected the blood samples from 18 healthy donors (HD) and 38 COVID-19 patients to analyze changes on γδ T cell population. In comparison with HD, the γδ T cell percentage decreased, while the activation marker CD25 expression increased in response to SARS-CoV-2 infection. Interestingly, the CD4 expression was upregulated in γδ T cells reflecting the occurrence of a specific effector cell population, which may serve as a biomarker for the assessment of SARS-CoV-2 infection.
Subject(s)
Coronavirus Infections/immunology , Pneumonia, Viral/immunology , T-Lymphocyte Subsets/immunology , Adult , Betacoronavirus/physiology , Biomarkers , CD4 Antigens/metabolism , COVID-19 , China , Flow Cytometry , Humans , Immunity, Innate , Interleukin-2 Receptor alpha Subunit/metabolism , Pandemics , SARS-CoV-2 , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/metabolismABSTRACT
Coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) has rapidly spread worldwide, threatening the health and lives of many people. Unfortunately, information regarding the immunological characteristics of COVID-19 patients remains limited. Herein, we collected blood samples from 18 healthy donors (HDs) and 38 COVID-19 patients to analyse changes in the adaptive immune cell populations and their phenotypes. We observed that the lymphocyte percentage moderately decreased, CD4 and CD8 T cell percentage among lymphocytes were similar, and B cell percentage was increased in COVID-19 patients in comparison to that in HDs. T cells, especially CD8 T cells, showed an enhanced expression of late activation marker CD25 and exhaustion marker PD-1. Importantly, SARS-CoV-2 infection increased the percentage of T follicular helper- and germinal centre B-like cells in the blood. The parameters in COVID-19 patients remained unchanged across various age groups. Therefore, we demonstrated that the T and B cells are activated naturally and are functional during SARS-CoV-2 infection. These data provide evidence that the adaptive immunity in most patients could be primed to induce a significant immune response against SARS-CoV-2 infection upon receiving standard medical care.