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1.
Front Immunol ; 12: 700152, 2021.
Article in English | MEDLINE | ID: covidwho-1359189

ABSTRACT

Background: Mucosal-associated invariant T (MAIT) cells are considered to participate of the host immune response against acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, single-cell transcriptomic profiling of MAIT cells in patients with COVID-19 remains unexplored. Methods: We performed single-cell RNA sequencing analyses on peripheral MAIT cells from 13 patients with COVID-19 and 5 healthy donors. The transcriptional profiles of MAIT cells, together with assembled T-cell receptor sequences, were analyzed. Flow cytometry analysis was also performed to investigate the properties of MAIT cells. Results: We identified that differentially expressed genes (DEGs) of MAIT cells were involved in myeloid leukocyte activation and lymphocyte activation in patients with COVID-19. In addition, in MAIT cells from severe cases, more DEGs were enriched in adaptive cellular and humoral immune responses compared with those in moderate cases. Further analysis indicated that the increase of cell cytotoxicity (killing), chemotaxis, and apoptosis levels in MAIT cells were consistent with disease severity and displayed the highest levels in patients with severe disease. Interestingly, flow cytometry analysis showed that the frequencies of pyroptotic MAIT cells, but not the frequencies of apoptotic MAIT cells, were increased significantly in patients with COVID-19, suggesting pyroptosis is one of leading causes of MAIT cell deaths during SARS-CoV-2 infection. Importantly, there were more clonal expansions of MAIT cells in severe cases than in moderate cases. Conclusions: The results of the present study suggest that MAIT cells are likely to be involved in the host immune response against SARS-CoV-2 infection. Simultaneously, the transcriptomic data from MAIT cells provides a deeper understanding of the immune pathogenesis of the disease.


Subject(s)
COVID-19/immunology , Mucosal-Associated Invariant T Cells/immunology , SARS-CoV-2/immunology , Transcriptome/genetics , Base Sequence , COVID-19/pathology , Gene Expression Profiling , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , Humans , Lymphocyte Activation/genetics , Pyroptosis/physiology , Sequence Analysis, RNA , Severity of Illness Index , VDJ Exons/genetics
2.
J Infect Dis ; 222(3): 510-511, 2020 07 06.
Article in English | MEDLINE | ID: covidwho-661219
4.
Signal Transduct Target Ther ; 5(1): 172, 2020 08 27.
Article in English | MEDLINE | ID: covidwho-733534

ABSTRACT

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Cord Blood Stem Cell Transplantation/methods , Coronavirus Infections/therapy , Hematopoietic Stem Cells/virology , Mesenchymal Stem Cell Transplantation/methods , Pneumonia, Viral/therapy , Adult , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Drug Combinations , Female , Glucocorticoids/therapeutic use , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Lopinavir , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiration, Artificial , Ritonavir , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome
5.
Nat Immunol ; 21(9): 1107-1118, 2020 09.
Article in English | MEDLINE | ID: covidwho-710376

ABSTRACT

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Betacoronavirus/immunology , Coronavirus Infections/immunology , Interferon Type I/metabolism , Pneumonia, Viral/immunology , Receptors, Immunologic/metabolism , Adolescent , Adult , Aged , Antigens, CD/genetics , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/genetics , Antigens, Differentiation, T-Lymphocyte/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , COVID-19 , Cohort Studies , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/immunology , GPI-Linked Proteins/metabolism , Humans , Interferon Type I/genetics , Interferon Type I/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , RNA-Seq , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , SARS-CoV-2 , Severity of Illness Index , Single-Cell Analysis
6.
Nat Commun ; 11(1): 3410, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-635899

ABSTRACT

COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Adult , Aged , Aged, 80 and over , Betacoronavirus/immunology , Biomarkers/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , COVID-19 , Chemotaxis, Leukocyte , China/epidemiology , Coronavirus Infections/blood , Coronavirus Infections/virology , Cytokines/blood , Female , Humans , Inflammation , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Leukocyte Count , Lung/immunology , Lung/virology , Lymphocyte Activation , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/virology , SARS-CoV-2
7.
Cell Metab ; 32(2): 188-202.e5, 2020 08 04.
Article in English | MEDLINE | ID: covidwho-612608

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.


Subject(s)
Coronavirus Infections/blood , Coronavirus Infections/pathology , Exosomes/metabolism , G(M3) Ganglioside/blood , Gangliosides/blood , Pneumonia, Viral/blood , Pneumonia, Viral/pathology , Adult , Aged , Betacoronavirus , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , COVID-19 , Diglycerides/blood , Female , Humans , Male , Metabolome/physiology , Metabolomics/methods , Middle Aged , Pandemics , SARS-CoV-2 , Sphingomyelins/blood , Tandem Mass Spectrometry , Young Adult
8.
Cell Death Differ ; 27(11): 3196-3207, 2020 11.
Article in English | MEDLINE | ID: covidwho-591591

ABSTRACT

SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-ß, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-ß and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Lymphocyte Activation/immunology , Myeloid-Derived Suppressor Cells/cytology , Pneumonia, Viral/virology , Adult , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , COVID-19 , Coronavirus Infections/immunology , Cytokines/metabolism , Disease Progression , Female , Humans , Inflammation/immunology , Myeloid-Derived Suppressor Cells/immunology , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2
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