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1.
Nat Commun ; 12(1): 1961, 2021 03 30.
Article in English | MEDLINE | ID: covidwho-1169399

ABSTRACT

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-ß, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-ß. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-ß, and is distracted from itself.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Transforming Growth Factor beta/immunology , Adult , Aged , Aged, 80 and over , COVID-19/virology , Female , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Interleukins/immunology , Male , Middle Aged , Plasma Cells/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
2.
Life Sci ; 276: 119437, 2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1157592

ABSTRACT

In Coronavirus disease 2019 (COVID-19), a decreased number of regulatory T (Treg) cells and their mediated factors lead to a hyperinflammatory state due to overactivation of the inflammatory cells and factors during the infection. In the current study, we evaluated the Nanocurcumin effects on the Treg cell population and corresponding factors in mild and severe COVID-19 patients. To investigate the Nanocurcumin effects, 80 COVID-19 patients (40 at the severe stage and 40 at the mild stage) were selected and classified into Nanocurcumin and placebo arms. In both the Nanocurcumin and placebo groups, the Treg cell frequency, the gene expression of Treg transcription factor forkhead box P3 (FoxP3), and cytokines (IL-10, IL-35, and TGF-ß), as well as the serum levels of cytokines were measured before and after treatment. In both mild and severe COVID-19 patients, Nanocurcumin could considerably upregulate the frequency of Treg cells, the expression levels of FoxP3, IL-10, IL-35, and TGF-ß, as well as the serum secretion levels of cytokines in the Nanocurcumin-treated group compared to the placebo group. The abovementioned factors were remarkably increased in the post-treatment with Nanocurcumin before pre-treatment conditions. By contrast, it has been observed no notable alteration in the placebo group. Our findings revealed the SinaCurcumin® effective function in a significant increase in the number of Treg cells and their mediated factors in the Nanocurcumin group than in the placebo group in both mild and severe patients. Hence, it would be an efficient therapeutic agent in rehabilitating COVID-19 infected patients.


Subject(s)
COVID-19/drug therapy , Curcumin/pharmacology , T-Lymphocytes, Regulatory/drug effects , Adult , Aged , COVID-19/immunology , COVID-19/virology , Cytokines/drug effects , Cytokines/immunology , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression/drug effects , Humans , Interleukin-10/immunology , Interleukins/immunology , Male , Middle Aged , Nanomedicine/methods , RNA, Viral/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Transforming Growth Factor beta/immunology
3.
Sci Immunol ; 5(53)2020 11 06.
Article in English | MEDLINE | ID: covidwho-999190

ABSTRACT

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-ß present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunologic Memory/immunology , Lung/immunology , Pneumonia, Viral/immunology , SARS-CoV-2/immunology , Age Factors , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions/immunology , Humans , Influenza, Human/immunology , Influenza, Human/metabolism , Influenza, Human/virology , Lung/metabolism , Lung/virology , Mice, Inbred C57BL , Orthomyxoviridae/immunology , Orthomyxoviridae/physiology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/virology , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , SARS-CoV-2/physiology , Transforming Growth Factor beta/immunology , Transforming Growth Factor beta/metabolism
4.
Sci Adv ; 6(31)2020 07.
Article in English | MEDLINE | ID: covidwho-725277

ABSTRACT

The outbreak of the highly contagious and deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), has posed a serious threat to public health across the globe, calling for the development of effective diagnostic markers and therapeutics. Here, we report a highly reliable severity diagnostic biomarker, acetylated 676th lysine transforming growth factor-beta-induced protein (TGFBIp K676Ac). TGFBIp K676Ac was consistently elevated in the blood of patients with SARS-CoV-2 pneumonia (n = 113), especially in patients in the intensive care unit (ICU) compared to non-ICU patients. Patients' blood samples showed increased cytokines and lymphopenia, which are exemplary indicators of SARS-CoV-2 pneumonia. Treatment with TGFBIp neutralizing antibodies suppressed the cytokine storm. The increased level of TGFBIp K676Ac in ICU patients suggests the promise of this protein as a reliable severity diagnostic biomarker for severe SARS-CoV-2 disease.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/diagnosis , Cytokine Release Syndrome/diagnosis , Extracellular Matrix Proteins/immunology , Leukocytes, Mononuclear/immunology , Pneumonia, Viral/diagnosis , Protein Processing, Post-Translational , Respiratory Insufficiency/diagnosis , Transforming Growth Factor beta/immunology , Acetylation , Antibodies, Neutralizing/pharmacology , Betacoronavirus/immunology , Biomarkers/blood , COVID-19 , Case-Control Studies , Coronavirus Infections/blood , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Extracellular Matrix Proteins/antagonists & inhibitors , Extracellular Matrix Proteins/genetics , Gene Expression , Humans , Intensive Care Units , Leukocyte Count , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology , Lung/blood supply , Lung/drug effects , Lung/pathology , Lung/virology , Lysine/metabolism , NF-kappa B/genetics , NF-kappa B/immunology , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Primary Cell Culture , Prognosis , Respiratory Insufficiency/blood , Respiratory Insufficiency/immunology , Respiratory Insufficiency/pathology , SARS-CoV-2 , Severity of Illness Index , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/genetics
5.
Biomed Pharmacother ; 128: 110316, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-436600

ABSTRACT

BACKGROUND: Pudilan (PDL), a four-herb prescription with the traditional function of heat-clearing and detoxifying, has been clinically used as an anti-SARS-CoV-2 infectory agent in China. PDL might also have therapeutic potentials for COVID-19 while the underlying mechanisms remain to be clarified. METHODS: We used network pharmacology analysis and selected 68 co-targeted genes/proteins as targets of both PDL and COVID-19. These co-targeted genes/proteins were predicted by SwissDock Server for their high-precision docking simulation, and analyzed by STRING for proteins to protein interaction (PPI), pathway and GO (gene ontology) enrichment. The therapeutic effect for PDL treatment on COVID-19 was validated by the TCMATCOV (TCM Anti COVID-19) platform. RESULTS: PDL might prevent the entrance of SARS-CoV-2 entry into cells by blocking the angiotensin-converting enzyme 2 (ACE2). It might inhibit the cytokine storm by affecting C-reactive protein (CRP), interferon-γ (IFN-γ), interleukin- 6 (IL-6), interleukin- 10 (IL-10), tumor necrosis factor (TNF), epidermal growth factor receptor (EGFR), C-C motif chemokine ligand 5 (CCL5), transforming growth factor-ß1 (TGFß1), and other proteins. PDL might moderate the immune system to shorten the course of the disease, delay disease progression, and reduce the mortality rate. CONCLUSION: PDL might have a therapeutic effect on COVID-19 through three aspects, including the moderate immune system, anti-inflammation, and anti-virus entry into cells.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus , Coronavirus Infections , Cytokine Release Syndrome , Drugs, Chinese Herbal/pharmacology , Pandemics , Pneumonia, Viral , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Anti-Inflammatory Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Humans , Immunologic Factors/pharmacology , Interferon-gamma/immunology , Interleukins/immunology , Molecular Docking Simulation , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Protein Interaction Maps , SARS-CoV-2 , Transforming Growth Factor beta/immunology
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