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1.
BMC Complement Med Ther ; 21(1): 141, 2021 May 12.
Article in English | MEDLINE | ID: covidwho-1388756

ABSTRACT

BACKGROUND: Herbal remedies of Echinacea purpurea tinctures are widely used today to reduce common cold respiratory tract infections. METHODS: Transcriptome, epigenome and kinome profiling allowed a systems biology level characterisation of genomewide immunomodulatory effects of a standardized Echinacea purpurea (L.) Moench extract in THP1 monocytes. RESULTS: Gene expression and DNA methylation analysis revealed that Echinaforce® treatment triggers antiviral innate immunity pathways, involving tonic IFN signaling, activation of pattern recognition receptors, chemotaxis and immunometabolism. Furthermore, phosphopeptide based kinome activity profiling and pharmacological inhibitor experiments with filgotinib confirm a key role for Janus Kinase (JAK)-1 dependent gene expression changes in innate immune signaling. Finally, Echinaforce® treatment induces DNA hypermethylation at intergenic CpG, long/short interspersed nuclear DNA repeat elements (LINE, SINE) or long termininal DNA repeats (LTR). This changes transcription of flanking endogenous retroviral sequences (HERVs), involved in an evolutionary conserved (epi) genomic protective response against viral infections. CONCLUSIONS: Altogether, our results suggest that Echinaforce® phytochemicals strengthen antiviral innate immunity through tonic IFN regulation of pattern recognition and chemokine gene expression and DNA repeat hypermethylated silencing of HERVs in monocytes. These results suggest that immunomodulation by Echinaforce® treatment holds promise to reduce symptoms and duration of infection episodes of common cold corona viruses (CoV), Severe Acute Respiratory Syndrome (SARS)-CoV, and new occurring strains such as SARS-CoV-2, with strongly impaired interferon (IFN) response and weak innate antiviral defense.


Subject(s)
COVID-19/drug therapy , Echinacea , Immunologic Factors/pharmacology , Monocytes/drug effects , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Gene Expression , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Interferons/drug effects , Phytotherapy , Plant Extracts/therapeutic use
3.
Viral Immunol ; 34(5): 342-351, 2021 06.
Article in English | MEDLINE | ID: covidwho-1343608

ABSTRACT

The spectrum of coronavirus disease 2019 (COVID-19) severity, related to cellular immune functions, has not been fully clarified yet. Therefore, this study aimed to investigate the alteration of peripheral blood cells in patients with COVID-19. The flow cytometric characterization of immune cell subset was performed on 69 COVID-19 patients and 21 healthy controls. These data were evaluated based on the disease severity. A total of 69 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were classified as asymptomatic infection (n = 14), nonsevere (n = 39), and severe (n = 16) groups. Decreased lymphocytes and increased CD14 + 4- monocytes are found in patients with severe COVID-19. Decreased CD4 expression level was observed in the monocytes of patients with severe COVID-19. The total lymphocytes, B and T lymphocytes, CD4+ cells and CD8+ cells, and natural killer (NK) and natural killer T (NKT) cells were found to be decreased in patients with severe COVID-19. The CD4+/CD8+ ratio was not significantly different between patients with COVID-19 and healthy controls. The percentage of activated T cells (CD3+HLA-DR+) and B cells (CD19+CD38+) was lower in patients with severe COVID-19. Age and CD4- monocytes were independent predictors of disease severity. The SARS-CoV-2 infection may affect lymphocyte subsets, resulting in decreased T and B cells, monocytes, and NK and NKT cells. Decreased CD4 expression level by monocytes was significantly correlated with disease severity. Further studies on the host immune response to SARS-CoV-2 infection are necessary to predict the disease severity and protect against the virus.


Subject(s)
CD4 Antigens/genetics , COVID-19/immunology , Immunity, Cellular , Lymphocyte Subsets/immunology , Monocytes/immunology , Severity of Illness Index , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/pathology , Female , Flow Cytometry , Hospitalization/statistics & numerical data , Humans , Lymphocyte Activation , Lymphocyte Count , Male , Middle Aged , Young Adult
4.
Sci Transl Med ; 13(598)2021 06 16.
Article in English | MEDLINE | ID: covidwho-1314110

ABSTRACT

Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated expansion of this cell subpopulation in publicly available transcriptomics data. Here, using published datasets, we show that the gene expression program associated with MS1 correlated with sepsis severity and was up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of MS1 cells, we developed a cellular model for inducing CD14+ MS1 monocytes from healthy bone marrow hematopoietic stem and progenitor cells (HSPCs). We found that plasma from patients with bacterial sepsis or COVID-19 induced myelopoiesis in HSPCs in vitro and expression of the MS1 gene program in monocytes and neutrophils that differentiated from these HSPCs. Furthermore, we found that plasma concentrations of IL-6, and to a lesser extent IL-10, correlated with increased myeloid cell output from HSPCs in vitro and enhanced expression of the MS1 gene program. We validated the requirement for these two cytokines to induce the MS1 gene program through CRISPR-Cas9 editing of their receptors in HSPCs. Using this cellular model system, we demonstrated that induced MS1 cells were broadly immunosuppressive and showed decreased responsiveness to stimulation with a synthetic RNA analog. Our in vitro study suggests a potential role for systemic cytokines in inducing myelopoiesis during severe bacterial or SARS-CoV-2 infection.


Subject(s)
COVID-19 , Hematopoietic Stem Cell Transplantation , Sepsis , Humans , Myeloid Cells , SARS-CoV-2
5.
Cell Res ; 31(8): 836-846, 2021 08.
Article in English | MEDLINE | ID: covidwho-1275907

ABSTRACT

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood-air barrier, blood-testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.


Subject(s)
COVID-19/pathology , Lung/virology , SARS-CoV-2/isolation & purification , Aged , Aged, 80 and over , Autopsy , COVID-19/virology , China , Cohort Studies , Critical Illness , Female , Fibrosis , Hospitalization , Humans , Kidney/pathology , Kidney/virology , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology , Lung/pathology , Male , Middle Aged , RNA, Viral/metabolism , SARS-CoV-2/genetics , Spleen/pathology , Spleen/virology , Trachea/pathology , Trachea/virology
6.
Clin Chem Lab Med ; 59(7): 1315-1322, 2021 Jun 25.
Article in English | MEDLINE | ID: covidwho-1278216

ABSTRACT

OBJECTIVES: Severe forms of coronavirus disease 2019 (COVID-19) are characterized by an excessive production of inflammatory cytokines. Activated monocytes secrete high levels of cytokines. Human monocytes are divided into three major populations: conventional (CD14posCD16neg), non-classical (CD14dimCD16pos), and intermediate (CD14posCD16pos) monocytes. The aim of this study was to analyze whether the distribution of conventional (CD16neg) and CD16pos monocytes is different in patients with COVID-19 and whether the variations could be predictive of the outcome of the disease. METHODS: We performed a prospective study on 390 consecutive patients referred to the Emergency Unit, with a proven diagnosis of SARS-CoV 2 infection by RT-PCR. Using the CytoDiff™ reagent, an automated routine leukocyte differential, we quantified CD16neg and CD16pos monocytes. RESULTS: In the entire population, median CD16neg and CD16pos monocyte levels (0.398 and 0.054×109/L, respectively) were in the normal range [(0.3-0.7×109/L) and (0.015-0.065×109/L), respectively], but the 35 patients in the intensive care unit (ICU) had a significantly (p<0.001) lower CD16pos monocyte count (0.018 × 109/L) in comparison to the 70 patients who were discharged (0.064 × 109/L) or were hospitalized in conventional units (0.058 × 109/L). By ROC curve analysis, the ratio [absolute neutrophil count/CD16pos monocyte count] was highly discriminant to identify patients requiring ICU hospitalization: with a cut-off 193.1, the sensitivity and the specificity were 74.3 and 81.8%, respectively (area under the curve=0.817). CONCLUSIONS: Quantification of CD16pos monocytes and the ratio [absolute neutrophil count/CD16pos monocyte count] could constitute a marker of the severity of disease in COVID-19 patients.


Subject(s)
COVID-19/diagnosis , Monocytes/cytology , Adult , Aged , Aged, 80 and over , Area Under Curve , Biomarkers/blood , COVID-19/blood , Female , Humans , Intensive Care Units/statistics & numerical data , Leukocyte Count/statistics & numerical data , Male , Middle Aged , Monocytes/classification , Prognosis , Prospective Studies , ROC Curve , SARS-CoV-2 , Young Adult
7.
Proc Natl Acad Sci U S A ; 118(26)2021 06 29.
Article in English | MEDLINE | ID: covidwho-1276011

ABSTRACT

Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1ß, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.


Subject(s)
Cell Hypoxia/immunology , Hypoxia-Inducible Factor 1, alpha Subunit/immunology , Monocytes/immunology , COVID-19/immunology , Cells, Cultured , Cytokines/immunology , Humans , Interferon Regulatory Factors/metabolism , Interferon Type I/immunology , Interferon Type I/metabolism , Interleukin-1beta/metabolism , Monocytes/metabolism , NF-kappa B/immunology , NF-kappa B/metabolism , Oxygen/metabolism , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/metabolism
8.
J Exp Med ; 218(8)2021 08 02.
Article in English | MEDLINE | ID: covidwho-1269483

ABSTRACT

Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.


Subject(s)
COVID-19/blood , COVID-19/immunology , Immunity, Innate/physiology , Adult , Aged , COVID-19/genetics , COVID-19/mortality , Case-Control Studies , Cytokines/genetics , Epigenesis, Genetic , Female , Hematopoiesis , Humans , Killer Cells, Natural/pathology , Killer Cells, Natural/virology , Male , Middle Aged , Monocytes/pathology , Monocytes/virology , NF-kappa B/metabolism , Neutrophils/pathology , Neutrophils/virology , Proteomics , Severity of Illness Index , Single-Cell Analysis
9.
Front Immunol ; 12: 665773, 2021.
Article in English | MEDLINE | ID: covidwho-1264333

ABSTRACT

The COVID-19 pandemic has caused more than three million deaths globally. The severity of the disease is characterized, in part, by a dysregulated immune response. CD16+ monocytes are innate immune cells involved in inflammatory responses to viral infections, and tissue repair, among other functions. We characterized the transcriptional changes in CD16+ monocytes from PBMC of people with COVID-19, and from healthy individuals using publicly available single cell RNA sequencing data. CD16+ monocytes from people with COVID-19 compared to those from healthy individuals expressed transcriptional changes indicative of increased cell activation, and induction of a migratory phenotype. We also analyzed COVID-19 cases based on severity of the disease and found that mild cases were characterized by upregulation of interferon response and MHC class II related genes, whereas the severe cases had dysregulated expression of mitochondrial and antigen presentation genes, and upregulated inflammatory, cell movement, and apoptotic gene signatures. These results suggest that CD16+ monocytes in people with COVID-19 contribute to a dysregulated host response characterized by decreased antigen presentation, and an elevated inflammatory response with increased monocytic infiltration into tissues. Our results show that there are transcriptomic changes in CD16+ monocytes that may impact the functions of these cells, contributing to the pathogenesis and severity of COVID-19.


Subject(s)
COVID-19/virology , Monocytes/virology , Receptors, IgG/metabolism , SARS-CoV-2/pathogenicity , Transcription, Genetic , Transcriptome , Adult , Aged , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , COVID-19/genetics , COVID-19/immunology , COVID-19/metabolism , Case-Control Studies , Cytokines/genetics , Cytokines/metabolism , Female , GPI-Linked Proteins/metabolism , Gene Expression Profiling , Host-Pathogen Interactions , Humans , Inflammation Mediators/metabolism , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/metabolism , Male , Middle Aged , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Monocytes/immunology , Monocytes/metabolism , RNA-Seq , SARS-CoV-2/immunology , Severity of Illness Index , Single-Cell Analysis , Young Adult
10.
Sci Transl Med ; 13(598)2021 06 16.
Article in English | MEDLINE | ID: covidwho-1262379

ABSTRACT

Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated expansion of this cell subpopulation in publicly available transcriptomics data. Here, using published datasets, we show that the gene expression program associated with MS1 correlated with sepsis severity and was up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of MS1 cells, we developed a cellular model for inducing CD14+ MS1 monocytes from healthy bone marrow hematopoietic stem and progenitor cells (HSPCs). We found that plasma from patients with bacterial sepsis or COVID-19 induced myelopoiesis in HSPCs in vitro and expression of the MS1 gene program in monocytes and neutrophils that differentiated from these HSPCs. Furthermore, we found that plasma concentrations of IL-6, and to a lesser extent IL-10, correlated with increased myeloid cell output from HSPCs in vitro and enhanced expression of the MS1 gene program. We validated the requirement for these two cytokines to induce the MS1 gene program through CRISPR-Cas9 editing of their receptors in HSPCs. Using this cellular model system, we demonstrated that induced MS1 cells were broadly immunosuppressive and showed decreased responsiveness to stimulation with a synthetic RNA analog. Our in vitro study suggests a potential role for systemic cytokines in inducing myelopoiesis during severe bacterial or SARS-CoV-2 infection.


Subject(s)
COVID-19 , Hematopoietic Stem Cell Transplantation , Sepsis , Humans , Myeloid Cells , SARS-CoV-2
11.
J Enzyme Inhib Med Chem ; 36(1): 1016-1028, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1226495

ABSTRACT

Elastase is a proteolytic enzyme belonging to the family of hydrolases produced by human neutrophils, monocytes, macrophages, and endothelial cells. Human neutrophil elastase is known to play multiple roles in the human body, but an increase in its activity may cause a variety of diseases. Elastase inhibitors may prevent the development of psoriasis, chronic kidney disease, respiratory disorders (including COVID-19), immune disorders, and even cancers. Among polyphenolic compounds, some flavonoids and their derivatives, which are mostly found in herbal plants, have been revealed to influence elastase release and its action on human cells. This review focuses on elastase inhibitors that have been discovered from natural sources and are biochemically characterised as flavonoids. The inhibitory activity on elastase is a characteristic of flavonoid aglycones and their glycoside and methylated, acetylated and hydroxylated derivatives. The presented analysis of structure-activity relationship (SAR) enables the determination of the chemical groups responsible for evoking an inhibitory effect on elastase. Further study especially of the in vivo efficacy and safety of the described natural compounds is of interest in order to gain better understanding of their health-promoting potential.


Subject(s)
Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Leukocyte Elastase/antagonists & inhibitors , Neutrophils/enzymology , COVID-19/drug therapy , COVID-19/metabolism , Enzyme Inhibitors/chemistry , Flavonoids/chemistry , Humans , Leukocyte Elastase/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Neutrophils/drug effects , Structure-Activity Relationship
12.
mBio ; 12(3)2021 05 04.
Article in English | MEDLINE | ID: covidwho-1216782

ABSTRACT

The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. In this study, we observed massive elevation of plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls (HCs). By using the receiver operating characteristic (ROC) curve, we found that a baseline of 2,042 pg/ml plasma Gal-9 can differentiate SARS-CoV-2-infected from noninfected individuals with high specificity/sensitivity (95%). Analysis of 30 cytokines and chemokines detected a positive correlation of the plasma Gal-9 with C-reactive protein (CRP) and proinflammatory cytokines/chemokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IP-10, MIP-1α, and MCP-1 but an inverse correlation with transforming growth factor ß (TGF-ß) in COVID-19 patients. In agreement, we found enhanced production of IL-6 and TNF-α by monocytes and NK cells of COVID-19 patients once treated with the recombinant human Gal-9 in vitro Also, we observed that although the cell-membrane expression of Gal-9 on monocytes does not change in COVID-19 patients, those with higher Gal-9 expression exhibit an activated phenotype. Furthermore, we noted significant downregulation of surface Gal-9 in neutrophils from COVID-19 patients compared to HCs. Our further investigations indicated that immune activation following SARS-CoV-2 infection results in Gal-9 shedding from neutrophils. The strong correlation of Gal-9 with proinflammatory mediators suggests that inhibition of Gal-9 may severe as a therapeutic approach in COVID-19 infection. Besides, the plasma Gal-9 measurement may be used as a surrogate diagnostic biomarker in COVID-19 patients.IMPORTANCE The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. We observed substantial elevation of the plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls. Gal-9 is an abundant protein in many immune and nonimmune cells. We found that Gal-9 detection assay can differentiate SARS-CoV-2-infected from noninfected individuals with a specificity/sensitivity of 95%. Importantly, we found a positive correlation of the plasma Gal-9 with a wide range of proinflammatory biomarkers in COVID-19 patients. In agreement, we found enhanced expression and production of such proinflammatory molecules by immune cells of COVID-19 patients once treated with Gal-9 in vitro Our results propose Gal-9 as an important contributing factor in cytokine release syndrome; therefore, Gal-9 inhibition may serve as a beneficial therapeutic approach by suppressing the hyperimmune activation in COVID-19 patients.


Subject(s)
Biomarkers/blood , COVID-19/blood , COVID-19/diagnosis , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/physiopathology , Galectins/blood , Sex Factors , Adult , Age Factors , Aged , Aged, 80 and over , Female , Healthy Volunteers , Humans , Male , Middle Aged , ROC Curve , SARS-CoV-2
13.
Front Med (Lausanne) ; 8: 655785, 2021.
Article in English | MEDLINE | ID: covidwho-1186838

ABSTRACT

Objectives: Several parameters aid in deciphering between viral and bacterial infections; however, new tools should be investigated in order to reduce the time to results and proceed with an early target-therapy. Validation of a biomarker study, including CD64 and CD169 expression, was conducted. Material and Methods: Patients with active SARS-CoV-2 infection (ACov-2), bacterial infection (ABI), healthy controls, and antiretroviral-controlled chronic HIV infection were assessed. Whole blood was stained and, after lysing no-wash protocol, acquired by flow cytometry. The median fluorescence intensity (MFI) of CD64 and CD169 was measured in granulocytes, monocytes, and lymphocytes. The CD64 MFI ratio granulocytes to lymphocytes (CD64N) and CD169 MFI ratio monocytes to lymphocytes (CD169Mo) were evaluated as biomarkers of acute bacterial and viral infection, respectively. Results: A CD64N ratio higher than 3.3 identified patients with ABI with 83.3 and 85.9% sensitivity and specificity, with an area under the curve (AUC) of 83.5%. In contrast, other analytic or hematological parameters used in the clinic had lower AUC compared with the CD64N ratio. Moreover, a CD169Mo ratio higher than 3.3 was able to identify ACov-2 with 91.7 and 89.8 sensitivity and specificity, with the highest AUC (92.0%). Conclusion: This work confirms the previous data of CD64N and CD169Mo ratios in an independent cohort, including controlled chronic viral HIV infection patients as biomarkers of acute bacterial and viral infections, respectively. Such an approach would benefit from quick pathogen identification for a direct-therapy with a clear application in different Health Care Units, especially during this COVID pandemic.

14.
Curr Res Transl Med ; 69(2): 103289, 2021 05.
Article in English | MEDLINE | ID: covidwho-1179993

ABSTRACT

Elevated PCT level in COVID-19 was associated with higher risk of severe disease and higher risk of overall mortality. An increased PCT level of PCT in COVID-19 patients especially in severe cases would be assumed as bacterial coinfection. Could PCT level increase in SARS-CoV-2 infection without bacterial coinfection? Several SARS-CoV-2 proteins activate STAT3-dependent transcriptional pathways particularly in monocytes, that could lead to increased PCT production. STAT3α isoform could cause increased ACE2 expression, resulting more SARS-CoV-2 infected cells and further production of PCT.


Subject(s)
Bacterial Infections/diagnosis , COVID-19/diagnosis , Coinfection/diagnosis , Procalcitonin/blood , SARS-CoV-2/immunology , Bacterial Infections/blood , Bacterial Infections/complications , Biomarkers/blood , COVID-19/blood , COVID-19/complications , COVID-19/immunology , Coinfection/blood , Coinfection/complications , Humans , Immunity/physiology , Monocytes/metabolism , Monocytes/virology , Predictive Value of Tests , Procalcitonin/metabolism , STAT3 Transcription Factor/metabolism , Severity of Illness Index , Signal Transduction/immunology
15.
Cell Death Discov ; 7(1): 43, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1111974

ABSTRACT

Infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with leukopenia and uncontrolled inflammatory response in critically ill patients. A better comprehension of SARS-CoV-2-induced monocyte death is essential for the identification of therapies capable to control the hyper-inflammation and reduce viral replication in patients with 2019 coronavirus disease (COVID-19). Here, we show that SARS-CoV-2 engages inflammasome and triggers pyroptosis in human monocytes, experimentally infected, and from patients under intensive care. Pyroptosis associated with caspase-1 activation, IL-1ß production, gasdermin D cleavage, and enhanced pro-inflammatory cytokine levels in human primary monocytes. At least in part, our results originally describe mechanisms by which monocytes, a central cellular component recruited from peripheral blood to respiratory tract, succumb to control severe COVID-19.

16.
J Infect Dis ; 223(4): 562-567, 2021 02 24.
Article in English | MEDLINE | ID: covidwho-1101848

ABSTRACT

We assessed the expression of CD169, a type I interferon-inducible receptor, on monocytes (monocyte CD169 [mCD169]) in 53 adult patients admitted to the hospital during the coronavirus disease 2019 (COVID-19) outbreak for a suspicion of severe acute respiratory syndrome coronavirus 2 infection. Monocyte CD169 was strongly overexpressed in 30 of 32 (93.7%) confirmed COVID-19 cases, compared with 3 of 21 (14.3%) patients in whom the diagnosis of COVID-19 was finally ruled out. Monocyte CD169 was associated with the plasma interferon-alpha level and thrombocytopenia. Monocyte CD169 testing may be helpful for the rapid triage of suspected COVID-19 patients during an outbreak.


Subject(s)
COVID-19/diagnosis , Monocytes/metabolism , Sialic Acid Binding Ig-like Lectin 1/metabolism , Aged , Biomarkers/metabolism , COVID-19/metabolism , Early Diagnosis , Female , Flow Cytometry , Humans , Male , Middle Aged , Monocytes/virology , ROC Curve
17.
Clin Chem Lab Med ; 59(7): 1315-1322, 2021 Jun 25.
Article in English | MEDLINE | ID: covidwho-1094090

ABSTRACT

OBJECTIVES: Severe forms of coronavirus disease 2019 (COVID-19) are characterized by an excessive production of inflammatory cytokines. Activated monocytes secrete high levels of cytokines. Human monocytes are divided into three major populations: conventional (CD14posCD16neg), non-classical (CD14dimCD16pos), and intermediate (CD14posCD16pos) monocytes. The aim of this study was to analyze whether the distribution of conventional (CD16neg) and CD16pos monocytes is different in patients with COVID-19 and whether the variations could be predictive of the outcome of the disease. METHODS: We performed a prospective study on 390 consecutive patients referred to the Emergency Unit, with a proven diagnosis of SARS-CoV 2 infection by RT-PCR. Using the CytoDiff™ reagent, an automated routine leukocyte differential, we quantified CD16neg and CD16pos monocytes. RESULTS: In the entire population, median CD16neg and CD16pos monocyte levels (0.398 and 0.054×109/L, respectively) were in the normal range [(0.3-0.7×109/L) and (0.015-0.065×109/L), respectively], but the 35 patients in the intensive care unit (ICU) had a significantly (p<0.001) lower CD16pos monocyte count (0.018 × 109/L) in comparison to the 70 patients who were discharged (0.064 × 109/L) or were hospitalized in conventional units (0.058 × 109/L). By ROC curve analysis, the ratio [absolute neutrophil count/CD16pos monocyte count] was highly discriminant to identify patients requiring ICU hospitalization: with a cut-off 193.1, the sensitivity and the specificity were 74.3 and 81.8%, respectively (area under the curve=0.817). CONCLUSIONS: Quantification of CD16pos monocytes and the ratio [absolute neutrophil count/CD16pos monocyte count] could constitute a marker of the severity of disease in COVID-19 patients.


Subject(s)
COVID-19/diagnosis , Monocytes/cytology , Adult , Aged , Aged, 80 and over , Area Under Curve , Biomarkers/blood , COVID-19/blood , Female , Humans , Intensive Care Units/statistics & numerical data , Leukocyte Count/statistics & numerical data , Male , Middle Aged , Monocytes/classification , Prognosis , Prospective Studies , ROC Curve , SARS-CoV-2 , Young Adult
18.
J Am Coll Nutr ; 40(4): 327-332, 2021.
Article in English | MEDLINE | ID: covidwho-1087590

ABSTRACT

Objective: Vitamin D deficiency is common in the general population and diabetic patients, and supplementation with vitamin D is widely used to help lower oxidative stress and inflammation. The cytokine storm in SARS-CoV2 infection has been linked with both diabetes and Vitamin D deficiency. This study examined the hypothesis that supplementation with vitamin D, in combination with l-cysteine (LC), is better at reducing oxidative stress and thereby, more effective, at inhibiting the secretion of the pro-inflammatory cytokines, Interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in U937 monocytes exposed to high glucose concentrations. Methods: U937 monocytes were pretreated with 1,25 (OH)2 vitamin D (VD, 10 nM) or LC (250 µM) or VD + LC for 24 h and then exposed to control or high glucose (HG, 25 mM) for another 24 h. Results: There were significantly greater reactive oxygen species (ROS) levels in monocytes treated with HG than those in controls. Combined supplementation with VD and LC showed a more significant reduction in ROS (46%) in comparison with treatment with LC (19%) or VD (26%) alone in monocytes exposed to HG. Similarly, VD supplementation, together with LC, caused a more significant inhibition in the secretion of IL-8 (36% versus 16%) and MCP-1 (46% versus 26%) in comparison with that of VD (10 nM) alone in high-glucose treated monocytes. Conclusions: These results suggest that combined supplementation with vitamin D and LC has the potential to be more effective than either VD or LC alone in lowering the risk of oxidative stress and inflammation associated with type 2 diabetes or COVID-19 infection. Further, this combined vitamin D with LC/N-acetylcysteine may be a potent alternative therapy for SARS-CoV2 infected subjects. This approach can prevent cellular damage due to cytokine storm in comorbid systemic inflammatory conditions, such as diabetes, obesity, and hypertension.


Subject(s)
COVID-19/drug therapy , Cysteine/administration & dosage , Oxidative Stress/drug effects , SARS-CoV-2/immunology , Vitamin D/administration & dosage , COVID-19/immunology , Chemokine CCL2/metabolism , Diabetes Mellitus, Type 2/drug therapy , Dietary Supplements , Drug Therapy, Combination , Glucose/administration & dosage , Humans , Interleukin-8/metabolism , Monocytes/immunology , Monocytes/virology , U937 Cells , Vitamin D Deficiency/drug therapy , Vitamin D Deficiency/immunology , Vitamin D Deficiency/virology
19.
Int J Infect Dis ; 101: 52-55, 2020 12.
Article in English | MEDLINE | ID: covidwho-1065166
20.
Cytometry A ; 99(5): 466-471, 2021 05.
Article in English | MEDLINE | ID: covidwho-1064342

ABSTRACT

During the second surge of COVID-19 in France (fall 2020), we assessed the expression of monocyte CD169 (i.e., Siglec-1, one of the numerous IFN-stimulated genes) upon admission to intensive care units of 45 patients with RT-PCR-confirmed SARS-CoV2 pulmonary infection. Overall, CD169 expression was strongly induced on circulating monocytes of COVID-19 patients compared with healthy donors and patients with bacterial sepsis. Beyond its contribution at the emergency department, CD169 testing may be also helpful for patients' triage at the ICU to rapidly reinforce suspicion of COVID-19 etiology in patients with acute respiratory failure awaiting for PCR results for definitive diagnosis.


Subject(s)
COVID-19/blood , Intensive Care Units , Monocytes/metabolism , Patient Admission , SARS-CoV-2/pathogenicity , Sialic Acid Binding Ig-like Lectin 1/blood , Adult , Aged , Biomarkers/blood , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , Female , Flow Cytometry , Host-Pathogen Interactions , Humans , Male , Middle Aged , Monocytes/immunology , Monocytes/virology , Predictive Value of Tests , Preliminary Data , Prognosis , Prospective Studies , SARS-CoV-2/immunology , Up-Regulation
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