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1.
Front Immunol ; 12: 807134, 2021.
Article in English | MEDLINE | ID: covidwho-1604257

ABSTRACT

ORF8 is a viral immunoglobulin-like (Ig-like) domain protein encoded by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA genome. It tends to evolve rapidly and interfere with immune responses. However, the structural characteristics of various coronavirus ORF8 proteins and their subsequent effects on biological functions remain unclear. Herein, we determined the crystal structures of SARS-CoV-2 ORF8 (S84) (one of the epidemic isoforms) and the bat coronavirus RaTG13 ORF8 variant at 1.62 Å and 1.76 Å resolution, respectively. Comparison of these ORF8 proteins demonstrates that the 62-77 residues in Ig-like domain of coronavirus ORF8 adopt different conformations. Combined with mutagenesis assays, the residue Cys20 of ORF8 is responsible for forming the covalent disulfide-linked dimer in crystal packing and in vitro biochemical conditions. Furthermore, immune cell-binding assays indicate that various ORF8 (SARS-CoV-2 ORF8 (L84), ORF8 (S84), and RaTG13 ORF8) proteins have different interaction capabilities with human CD14+ monocytes in human peripheral blood. These results provide new insights into the specific characteristics of various coronavirus ORF8 and suggest that ORF8 variants may influence disease-related immune responses.


Subject(s)
COVID-19/immunology , Chiroptera/immunology , Immunity/immunology , Immunoglobulin Domains/immunology , Viral Proteins/immunology , Animals , Binding Sites/genetics , COVID-19/virology , Cells, Cultured , Chiroptera/genetics , Chiroptera/metabolism , Crystallography, X-Ray , Humans , Immunity/genetics , Immunoglobulin Domains/genetics , Lipopolysaccharide Receptors/immunology , Lipopolysaccharide Receptors/metabolism , Models, Molecular , Monocytes/immunology , Monocytes/metabolism , Mutation , Protein Binding , Species Specificity , Viral Proteins/classification , Viral Proteins/genetics
2.
Proc Natl Acad Sci U S A ; 119(1)2022 01 04.
Article in English | MEDLINE | ID: covidwho-1595265

ABSTRACT

Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes a potentially fatal pneumonia with multiorgan failure, and high systemic inflammation. To gain mechanistic insight and ferret out the root of this immune dysregulation, we modeled, by in vitro coculture, the interactions between infected epithelial cells and immunocytes. A strong response was induced in monocytes and B cells, with a SARS-CoV-2-specific inflammatory gene cluster distinct from that seen in influenza A or Ebola virus-infected cocultures, and which reproduced deviations reported in blood or lung myeloid cells from COVID-19 patients. A substantial fraction of the effect could be reproduced after individual transfection of several SARS-CoV-2 proteins (Spike and some nonstructural proteins), mediated by soluble factors, but not via transcriptional induction. This response was greatly muted in monocytes from healthy children, perhaps a clue to the age dependency of COVID-19. These results suggest that the inflammatory malfunction in COVID-19 is rooted in the earliest perturbations that SARS-CoV-2 induces in epithelia.


Subject(s)
COVID-19/immunology , Epithelial Cells/immunology , Monocytes/immunology , SARS-CoV-2/pathogenicity , Adult , B-Lymphocytes/immunology , COVID-19/pathology , Child , Coculture Techniques , Ebolavirus/pathogenicity , Epithelial Cells/virology , Gene Expression Profiling , Humans , Inflammation , Influenza A virus/pathogenicity , Lung/immunology , Myeloid Cells/immunology , Species Specificity , Viral Proteins/immunology
3.
Nat Immunol ; 23(1): 23-32, 2022 01.
Article in English | MEDLINE | ID: covidwho-1585822

ABSTRACT

Systemic immune cell dynamics during coronavirus disease 2019 (COVID-19) are extensively documented, but these are less well studied in the (upper) respiratory tract, where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates1-6. Here, we characterized nasal and systemic immune cells in individuals with COVID-19 who were hospitalized or convalescent and compared the immune cells to those seen in healthy donors. We observed increased nasal granulocytes, monocytes, CD11c+ natural killer (NK) cells and CD4+ T effector cells during acute COVID-19. The mucosal proinflammatory populations positively associated with peripheral blood human leukocyte antigen (HLA)-DRlow monocytes, CD38+PD1+CD4+ T effector (Teff) cells and plasmablasts. However, there was no general lymphopenia in nasal mucosa, unlike in peripheral blood. Moreover, nasal neutrophils negatively associated with oxygen saturation levels in blood. Following convalescence, nasal immune cells mostly normalized, except for CD127+ granulocytes and CD38+CD8+ tissue-resident memory T cells (TRM). SARS-CoV-2-specific CD8+ T cells persisted at least 2 months after viral clearance in the nasal mucosa, indicating that COVID-19 has both transient and long-term effects on upper respiratory tract immune responses.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Nasopharynx/immunology , Nose/cytology , Respiratory Mucosa/immunology , SARS-CoV-2/immunology , Antibodies, Viral/blood , COVID-19/immunology , COVID-19/pathology , Granulocytes/immunology , HLA-DR Antigens/metabolism , Humans , Killer Cells, Natural/immunology , Monocytes/immunology , Nasopharynx/cytology , Nasopharynx/virology , Neutrophils/immunology , Nose/immunology , Nose/virology , Prospective Studies , Respiratory Mucosa/cytology , Respiratory Mucosa/virology
4.
Virology ; 565: 73-81, 2022 01 02.
Article in English | MEDLINE | ID: covidwho-1545481

ABSTRACT

Bacillus Calmette-Guérin (BCG) vaccine is currently used to prevent tuberculosis infection. The vaccine was found to enhance resistance to certain types of infection including positive sense RNA viruses. The current COVID-19 pandemic is caused by positive sense RNA, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A higher mortality rate of COVID-19 patients was reported in countries where BCG vaccination is not routinely administered, when compared to the vaccinated ones. We hypothesized that BCG vaccine may control SARS-CoV2 infection via modulating the monocyte immune response. We analyzed GSE104149 dataset to investigate whether human monocytes of BCG-vaccinated individuals acquire resistance to SARS-CoV-2 infection. Differentially expressed genes obtained from the dataset were used to determine enriched pathways, biological processes, and molecular functions for monocytes post BCG vaccination. Our data show that BCG vaccine promotes a more effective immune response of monocytes against SARS-CoV2, but probably not sufficient to prevent the infection.


Subject(s)
BCG Vaccine/immunology , COVID-19/epidemiology , Vaccination/statistics & numerical data , BCG Vaccine/administration & dosage , COVID-19/prevention & control , Gene Expression Profiling , Humans , Inflammation , Monocytes/immunology , Monocytes/virology , SARS-CoV-2/physiology
5.
Elife ; 102021 07 22.
Article in English | MEDLINE | ID: covidwho-1513065

ABSTRACT

Immature neutrophils and HLA-DRneg/low monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored. We found an expansion of circulating immature CD16+CD66b+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4+CD28null T-cells. Notably, the expansion of circulating CD4+CD28null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools, we identified a tight relationship among the peripheral expansion of immature CD10neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10neg neutrophils enhanced IFN-γ production by CD4+ T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DRneg/low monocytes do not suppress T-cell proliferation but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Lastly, using a mouse model of AMI, we showed that immature neutrophils (CD11bposLy6GposCD101neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion. In conclusion, immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , HLA-DR Antigens/immunology , Monocytes/immunology , Myocardial Infarction/immunology , Neprilysin/immunology , Neutrophils/immunology , Aged , Animals , Biomarkers , Cell Differentiation , Cell Proliferation , Cytokines , Female , Humans , Inflammation , Lymphocyte Activation , Male , Mice , Middle Aged , Myocardial Infarction/pathology , T-Lymphocytes/immunology
6.
Front Immunol ; 12: 760288, 2021.
Article in English | MEDLINE | ID: covidwho-1488433

ABSTRACT

Both age and obesity are leading risk factors for severe coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Specifically, although most infections occur in individuals under the age of 55 years, 95% of hospitalizations, admissions to the intensive care unit, and deaths occur in those over the age of 55 years. Moreover, hospitalized COVID-19 patients have a higher prevalence of obesity. It is generally believed that chronic low-grade inflammation and dysregulated innate and adaptive immune responses that are associated with aging and obesity are responsible for this elevated risk of severe disease. However, the impact of advanced age and obesity on the host response to SARS-CoV-2 infection remains poorly defined. In this study, we assessed changes in the concentration of soluble immune mediators, IgG antibody titers, frequency of circulating immune cells, and cytokine responses to mitogen stimulation as a function of BMI and age. We detected significant negative correlations between BMI and myeloid immune cell subsets that were more pronounced in aged patients. Similarly, inflammatory cytokine production by monocytes was also negatively correlated with BMI in aged patients. These data suggest that the BMI-dependent impact on host response to SARS-CoV-2 is more pronounced on innate responses of aged patients.


Subject(s)
Aging/immunology , Body Mass Index , COVID-19/pathology , Obesity/pathology , SARS-CoV-2/immunology , Adaptive Immunity , Adult , Aged , Aged, 80 and over , Antibodies, Viral/immunology , Cytokines/immunology , Female , Hospitalization , Humans , Immunity, Innate , Linear Models , Male , Middle Aged , Monocytes/immunology , Young Adult
7.
J Immunol Res ; 2021: 8669098, 2021.
Article in English | MEDLINE | ID: covidwho-1476888

ABSTRACT

Objective: This study explored the consistency and differences in the immune cells and cytokines between patients with COVID-19 or cancer. We further analyzed the correlations between the acute inflammation and cancer-related immune disorder. Methods: This retrospective study involved 167 COVID-19 patients and 218 cancer patients. COVID-19 and cancer were each further divided into two subgroups. Quantitative and qualitative variables were measured by one-way ANOVA and chi-square test, respectively. Herein, we carried out a correlation analysis between immune cells and cytokines and used receiver operating characteristic (ROC) curves to discover the optimal diagnostic index. Results: COVID-19 and cancers were associated with lymphopenia and high levels of monocytes, neutrophils, IL-6, and IL-10. IL-2 was the optimal indicator to differentiate the two diseases. Compared with respiratory cancer patients, COVID-19 patients had lower levels of IL-2 and higher levels of CD3+CD4+ T cells and CD19+ B cells. In the subgroup analysis, IL-6 was the optimal differential diagnostic parameter that had the ability to identify if COVID-19 patients would be severely affected, and severe COVID-19 patients had lower levels of lymphocyte subsets (CD3+ T cells, CD3+CD4+ T cells, CD3+CD8+T cells, and CD19+ B cells) and CD16+CD56+ NK cells and higher level of neutrophils. There were significant differences in the levels of CD3+CD4+ T cells and CD19+ B cells between T1-2 and T3-4 stages as well as IL-2 and CD19+ B cells between N0-1 and N2-3 stages while no significant differences between the metastatic and nonmetastatic cancer patients. Additionally, there were higher correlations between IL-2 and IL-4, TNF-α and IL-2, TNF-α and IL-4, TNF-α and IFN-γ, and CD16+CD56+NK cells and various subsets of T cells in COVID-19 patients. There was a higher correlation between CD3+CD4+ T cells and CD19+ B cells in cancer patients. Conclusion: Inflammation associated with COVID-19 or cancer had effects on patients' outcomes. Accompanied by changes in immune cells and cytokines, there were consistencies, differences, and satisfactory correlations between patients with COVID-19 and those with cancers.


Subject(s)
COVID-19/immunology , Cytokines/blood , Lymphopenia/blood , Monocytes/immunology , Neoplasms/immunology , Neutrophils/immunology , Adolescent , Adult , Aged , Aged, 80 and over , B-Lymphocytes/immunology , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , COVID-19/diagnosis , COVID-19/pathology , Female , Humans , Inflammation/blood , Inflammation/pathology , Killer Cells, Natural/immunology , Lymphocyte Subsets/immunology , Male , Middle Aged , Neoplasms/diagnosis , Neoplasms/pathology , Retrospective Studies , SARS-CoV-2/immunology , Young Adult
8.
Sci Rep ; 11(1): 20254, 2021 10 12.
Article in English | MEDLINE | ID: covidwho-1467135

ABSTRACT

Monocytes are thought to play an important role in host defence and pathogenesis of COVID-19. However, a comprehensive examination of monocyte numbers and function has not been performed longitudinally in acute and convalescent COVID-19. We examined the absolute counts of monocytes, the frequency of monocyte subsets, the plasma levels of monocyte activation markers using flowcytometry and ELISA in seven groups of COVID-19 individuals, classified based on days since RT-PCR confirmation of SARS-CoV2 infection. Our data shows that the absolute counts of total monocytes and the frequencies of intermediate and non-classical monocytes increases from Days 15-30 to Days 61-90 and plateau thereafter. In contrast, the frequency of classical monocytes decreases from Days 15-30 till Days 121-150. The plasma levels of sCD14, CRP, sCD163 and sTissue Factor (sTF)-all decrease from Days 15-30 till Days 151-180. COVID-19 patients with severe disease exhibit higher levels of monocyte counts and higher frequencies of classical monocytes and lower frequencies of intermediate and non-classical monocytes and elevated plasma levels of sCD14, CRP, sCD163 and sTF in comparison with mild disease. Thus, our study provides evidence of dynamic alterations in monocyte counts, subset frequencies and activation status in acute and convalescent COVID-19 individuals.


Subject(s)
COVID-19/immunology , Monocytes , Acute Disease , Adolescent , Adult , Aged , Biomarkers/blood , Convalescence , Female , Humans , Leukocyte Count , Male , Middle Aged , Monocytes/cytology , Monocytes/immunology , Young Adult
9.
PLoS Pathog ; 17(10): e1009742, 2021 10.
Article in English | MEDLINE | ID: covidwho-1456098

ABSTRACT

Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage-HLADR+ cells lacking DC markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Regeneration/immunology , SARS-CoV-2/immunology , Adult , Antigens, CD/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , COVID-19/pathology , Dendritic Cells/pathology , Female , Humans , Male , Middle Aged , Monocytes/immunology , Monocytes/pathology , Programmed Cell Death 1 Receptor/immunology
10.
Front Immunol ; 12: 709759, 2021.
Article in English | MEDLINE | ID: covidwho-1450807

ABSTRACT

The clinical features of SARS-CoV-2 infection range from asymptomatic to severe disease with life-threatening complications. Understanding the persistence of immune responses in asymptomatic individuals merit special attention because of their importance in controlling the spread of the infections. We here studied the antibody and T cell responses, and a wide range of inflammation markers, in 56 SARS-CoV-2 antibody-positive individuals, identified by a population screen after the first wave of SARS-CoV-2 infection. These, mostly asymptomatic individuals, were reanalyzed 7-8 months after their infection together with 115 age-matched seronegative controls. We found that 7-8 months after the infection their antibodies to SARS-CoV-2 Nucleocapsid (N) protein declined whereas we found no decrease in the antibodies to Spike receptor-binding domain (S-RBD) when compared to the findings at seropositivity identification. In contrast to antibodies to N protein, the antibodies to S-RBD correlated with the viral neutralization capacity and with CD4+ T cell responses as measured by antigen-specific upregulation of CD137 and CD69 markers. Unexpectedly we found the asymptomatic antibody-positive individuals to have increased serum levels of S100A12, TGF-alpha, IL18, and OSM, the markers of activated macrophages-monocytes, suggesting long-term persistent inflammatory effect associated with the viral infection in asymptomatic individuals. Our results support the evidence for the long-term persistence of the inflammation process and the need for post-infection clinical monitoring of SARS-CoV-2 infected asymptomatic individuals.


Subject(s)
Antibodies, Viral/blood , Asymptomatic Infections , CD4-Positive T-Lymphocytes/immunology , COVID-19/pathology , Inflammation Mediators/blood , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , CD4 Lymphocyte Count , Coronavirus Nucleocapsid Proteins/immunology , Humans , Inflammation/immunology , Interleukin-18/blood , Macrophages/immunology , Monocytes/immunology , Oncostatin M/blood , Phosphoproteins/immunology , Protein Domains/immunology , S100A12 Protein/blood , Spike Glycoprotein, Coronavirus/immunology , Transforming Growth Factor alpha/blood
11.
Front Immunol ; 12: 705646, 2021.
Article in English | MEDLINE | ID: covidwho-1450806

ABSTRACT

COVID-19 is a disease with a spectrum of clinical responses ranging from moderate to critical. To study and control its effects, a large number of researchers are focused on two substantial aims. On the one hand, the discovery of diverse biomarkers to classify and potentially anticipate the disease severity of patients. These biomarkers could serve as a medical criterion to prioritize attention to those patients with higher prone to severe responses. On the other hand, understanding how the immune system orchestrates its responses in this spectrum of disease severities is a fundamental issue required to design new and optimized therapeutic strategies. In this work, using single-cell RNAseq of bronchoalveolar lavage fluid of nine patients with COVID-19 and three healthy controls, we contribute to both aspects. First, we presented computational supervised machine-learning models with high accuracy in classifying the disease severity (moderate and severe) in patients with COVID-19 starting from single-cell data from bronchoalveolar lavage fluid. Second, we identified regulatory mechanisms from the heterogeneous cell populations in the lungs microenvironment that correlated with different clinical responses. Given the results, patients with moderate COVID-19 symptoms showed an activation/inactivation profile for their analyzed cells leading to a sequential and innocuous immune response. In comparison, severe patients might be promoting cytotoxic and pro-inflammatory responses in a systemic fashion involving epithelial and immune cells without the possibility to develop viral clearance and immune memory. Consequently, we present an in-depth landscape analysis of how transcriptional factors and pathways from these heterogeneous populations can regulate their expression to promote or restrain an effective immune response directly linked to the patients prognosis.


Subject(s)
Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , COVID-19/pathology , Lung/cytology , SARS-CoV-2/immunology , B-Lymphocytes/immunology , Biomarkers , Bronchoalveolar Lavage Fluid/chemistry , Dendritic Cells/immunology , Epithelial Cells/cytology , Epithelial Cells/virology , Humans , Killer Cells, Natural/immunology , Lung/chemistry , Machine Learning , Macrophages/immunology , Monocytes/immunology , Neutrophils/immunology , RNA, Viral/genetics , Sequence Analysis, RNA , Severity of Illness Index , Single-Cell Analysis , T-Lymphocytes/immunology
12.
Dis Markers ; 2021: 6803510, 2021.
Article in English | MEDLINE | ID: covidwho-1443673

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most significant public health threat worldwide. Patients with severe COVID-19 usually have pneumonia concomitant with local inflammation and sometimes a cytokine storm. Specific components of the SARS-CoV-2 virus trigger lung inflammation, and recruitment of immune cells to the lungs exacerbates this process, although much remains unknown about the pathogenesis of COVID-19. Our study of lung type II pneumocyte cells (A549) demonstrated that ORF7, an open reading frame (ORF) in the genome of SARS-CoV-2, induced the production of CCL2, a chemokine that promotes the chemotaxis of monocytes, and decreased the expression of IL-8, a chemokine that recruits neutrophils. A549 cells also had an increased level of IL-6. The results of our chemotaxis Transwell assay suggested that ORF7 augmented monocyte infiltration and reduced the number of neutrophils. We conclude that the ORF7 of SARS-CoV-2 may have specific effects on the immunological changes in tissues after infection. These results suggest that the functions of other ORFs of SARS-CoV-2 should also be comprehensively examined.


Subject(s)
COVID-19/metabolism , Chemotaxis , Monocytes/pathology , Neutrophils/pathology , Open Reading Frames/physiology , Pneumonia/pathology , Viral Proteins/metabolism , A549 Cells , Chemokine CCL2/metabolism , Humans , In Vitro Techniques , Monocytes/immunology , Monocytes/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Pneumonia/immunology , Pneumonia/metabolism , SARS-CoV-2/metabolism , Viral Proteins/genetics
13.
Viruses ; 13(9)2021 09 10.
Article in English | MEDLINE | ID: covidwho-1430973

ABSTRACT

Monocytes are key modulators in acute viral infections, determining both inflammation and development of specific B- and T-cell responses. Recently, these cells were shown to be associated to different SARS-CoV-2 infection outcome. However, their role in acute HIV-1 infection remains unclear. We had the opportunity to evaluate the mononuclear cell compartment in an early hyper-acute HIV-1 patient in comparison with an untreated chronic HIV-1 and a cohort of SARS-CoV-2 infected patients, by high dimensional flow cytometry using an unsupervised approach. A distinct polarization of the monocyte phenotype was observed in the two viral infections, with maintenance of pro-inflammatory M1-like profile in HIV-1, in contrast to the M2-like immunosuppressive shift in SARS-CoV-2. Noticeably, both acute infections had reduced CD14low/-CD16+ non-classical monocytes, with depletion of the population expressing Slan (6-sulfo LacNac), which is thought to contribute to immune surveillance through pro-inflammatory properties. This depletion indicates a potential role of these cells in acute viral infection, which has not previously been explored. The inflammatory state accompanied by the depletion of Slan+ monocytes may provide new insights on the critical events that determine the rate of viral set-point in acute HIV-1 infection and subsequent impact on transmission and reservoir establishment.


Subject(s)
Amino Sugars/immunology , COVID-19/immunology , HIV Infections/immunology , HIV-1/immunology , Monocytes/immunology , Adult , Aged , Cohort Studies , Female , Humans , Leukocyte Count , Male , Middle Aged , Young Adult
14.
Front Immunol ; 12: 715072, 2021.
Article in English | MEDLINE | ID: covidwho-1430697

ABSTRACT

Background: Prediction of the severity of COVID-19 at its onset is important for providing adequate and timely management to reduce mortality. Objective: To study the prognostic value of damage parameters and cytokines as predictors of severity of COVID-19 using an extensive immunologic profiling and unbiased artificial intelligence methods. Methods: Sixty hospitalized COVID-19 patients (30 moderate and 30 severe) and 17 healthy controls were included in the study. The damage indicators high mobility group box 1 (HMGB1), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), extensive biochemical analyses, a panel of 47 cytokines and chemokines were analyzed at weeks 1, 2 and 7 along with clinical complaints and CT scans of the lungs. Unbiased artificial intelligence (AI) methods (logistic regression and Support Vector Machine and Random Forest algorithms) were applied to investigate the contribution of each parameter to prediction of the severity of the disease. Results: On admission, the severely ill patients had significantly higher levels of LDH, IL-6, monokine induced by gamma interferon (MIG), D-dimer, fibrinogen, glucose than the patients with moderate disease. The levels of macrophage derived cytokine (MDC) were lower in severely ill patients. Based on artificial intelligence analysis, eight parameters (creatinine, glucose, monocyte number, fibrinogen, MDC, MIG, C-reactive protein (CRP) and IL-6 have been identified that could predict with an accuracy of 83-87% whether the patient will develop severe disease. Conclusion: This study identifies the prognostic factors and provides a methodology for making prediction for COVID-19 patients based on widely accepted biomarkers that can be measured in most conventional clinical laboratories worldwide.


Subject(s)
COVID-19/pathology , Diagnosis, Computer-Assisted/methods , Severity of Illness Index , Support Vector Machine , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Biomarkers/analysis , Cytokines/blood , Female , HMGB1 Protein/blood , Humans , L-Lactate Dehydrogenase/blood , Macrophages/immunology , Male , Middle Aged , Monocytes/immunology , Prognosis , Prospective Studies , SARS-CoV-2
15.
Clin Rev Allergy Immunol ; 60(2): 259-270, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1384600

ABSTRACT

Ultraviolet blood irradiation (UBI) was used with success in the 1930s and 1940s for a variety of diseases. Despite the success, the lack of understanding of the detailed mechanisms of actions, and the achievements of antibiotics, phased off the use of UBI from the 1950s. The emergence of novel viral infections, from HIV/AIDS to Ebola, from SARS and MERS, and SARS-CoV-2, bring back the attention to this therapeutical opportunity. UBI has a complex virucidal activity, mostly acting on the immune system response. It has effects on lymphocytes (T-cells and B-cells), macrophages, monocytes, dendritic cells, low-density lipoprotein (LDL), and lipids. The Knott technique was applied for bacterial infections such as tuberculosis to viral infections such as hepatitis or influenza. The more complex extracorporeal photopheresis (ECP) is also being applied to hematological cancers such as T-cell lymphomas. Further studies of UBI may help to create a useful device that may find applications for novel viruses that are resistant to known antivirals or vaccines, or also bacteria that are resistant to known antibiotics.


Subject(s)
COVID-19/therapy , Photopheresis/methods , SARS-CoV-2/radiation effects , Ultraviolet Rays , Bacteria/radiation effects , Bacterial Infections/microbiology , Bacterial Infections/therapy , COVID-19/virology , Cytokines/metabolism , Dendritic Cells/immunology , Dendritic Cells/radiation effects , Humans , Lymphocytes/immunology , Lymphocytes/radiation effects , Macrophages/immunology , Macrophages/radiation effects , Monocytes/immunology , Monocytes/radiation effects , Signal Transduction/immunology , Signal Transduction/radiation effects , Treatment Outcome
16.
Cardiovasc Res ; 117(1): 224-239, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1387842

ABSTRACT

AIMS: To elucidate the prognostic role of monocytes in the immune response of patients with coronary artery disease (CAD) at risk for life-threatening heart and lung injury as major complications of SARS-CoV-2 infection. METHODS AND RESULTS: From February to April 2020, we prospectively studied a cohort of 96 participants comprising 47 consecutive patients with CAD and acute SARS-CoV-2 infection (CAD + SARS-CoV-2), 19 CAD patients without infections, and 30 healthy controls. Clinical assessment included blood sampling, echocardiography, and electrocardiography within 12 h of admission. Respiratory failure was stratified by the Horovitz Index (HI) as moderately/severely impaired when HI ≤200 mmHg. The clinical endpoint (EP) was defined as HI ≤200 mmHg with subsequent mechanical ventilation within a follow-up of 30 days. The numbers of CD14dimCD16+ non-classical monocytes in peripheral blood were remarkably low in CAD + SARS-CoV-2 compared with CAD patients without infection and healthy controls (P < 0.0001). Moreover, these CD14dimCD16 monocytes showed decreased expression of established markers of adhesion, migration, and T-cell activation (CD54, CD62L, CX3CR1, CD80, and HLA-DR). Decreased numbers of CD14dimCD16+ monocytes were associated with the occurrence of EP. Kaplan-Meier curves illustrate that CAD + SARS-CoV-2 patients with numbers below the median of CD14dimCD16+ monocytes (median 1443 cells/mL) reached EP significantly more often compared to patients with numbers above the median (log-rank 5.03, P = 0.025). CONCLUSION: Decreased numbers of CD14dimCD16+ monocytes are associated with rapidly progressive respiratory failure in CAD + SARS-CoV-2 patients. Intensified risk assessments comprising monocyte sub- and phenotypes may help to identify patients at risk for respiratory failure.


Subject(s)
COVID-19/complications , Coronary Artery Disease/complications , Lipopolysaccharide Receptors/analysis , Monocytes/physiology , Receptors, IgG/analysis , SARS-CoV-2 , Aged , Aged, 80 and over , COVID-19/immunology , Coronary Artery Disease/immunology , Female , GPI-Linked Proteins/analysis , Humans , Immunohistochemistry , Male , Middle Aged , Monocytes/immunology , Phenotype , Retrospective Studies
18.
Cytometry A ; 97(9): 887-890, 2020 09.
Article in English | MEDLINE | ID: covidwho-1384155

ABSTRACT

In patients with severe SARS-CoV-2 infection, the development of cytokine storm induces extensive lung damage, and monocytes play a role in this pathological process. Non-classical (NC) and intermediate (INT) monocytes are known to be involved during viral and bacterial infections. In this study, 30 patients with different manifestations of acute SARS-CoV-2 infection were investigated with a flow cytometric study of NC, INT, and classical (CL) monocytes. Significantly reduced NC and INT monocytes and a downregulated HLA-DR were found in acute patients with severe SARS-CoV-2 symptoms. Conversely in patients with moderate symptoms NC and INT monocytes and CD11b expression were increased. © 2020 International Society for Advancement of Cytometry.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Monocytes/immunology , Pneumonia, Viral/immunology , Aged , Betacoronavirus/pathogenicity , Biomarkers/analysis , CD11b Antigen/analysis , COVID-19 , Cell Separation , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Female , Flow Cytometry , Host Microbial Interactions , Humans , Leukocytes , Male , Middle Aged , Monocytes/virology , Pandemics , Phenotype , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , SARS-CoV-2 , Severity of Illness Index
19.
J Immunol ; 207(7): 1848-1856, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1377034

ABSTRACT

Immune cell responses are strikingly altered in patients with severe coronavirus disease 2019 (COVID-19), but the immunoregulatory process in these individuals is not fully understood. In this study, 23 patients with mild and 22 patients with severe COVID-19 and 6 asymptomatic carriers of COVID-19 were enrolled, along with 44 healthy controls (HC). Peripheral immune cells in HC and patients with COVID-19 were comprehensively profiled using mass cytometry. We found that in patients with severe COVID-19, the number of HLA-DRlow/- monocytes was significantly increased, but that of mucosal-associated invariant T (MAIT) cells was greatly reduced. MAIT cells were highly activated but functionally impaired in response to Escherichia coli and IL-12/IL-18 stimulation in patients with severe COVID-19, especially those with microbial coinfection. Single-cell transcriptome analysis revealed that IFN-stimulated genes were significantly upregulated in peripheral MAIT cells and monocytes from patients with severe COVID-19. IFN-α pretreatment suppressed MAIT cells' response to E. coli by triggering high levels of IL-10 production by HLA-DRlow/--suppressive monocytes. Blocking IFN-α or IL-10 receptors rescued MAIT cell function in patients with severe COVID-19. Moreover, plasma from patients with severe COVID-19 inhibited HLA-DR expression by monocytes through IL-10. These data indicate a unique pattern of immune dysregulation in severe COVID-19, which is characterized by enrichment of suppressive HLA-DRlow/- monocytes associated with functional impairment of MAIT cells through the IFN/IL-10 pathway.


Subject(s)
COVID-19/immunology , Escherichia coli Infections/immunology , Escherichia coli/physiology , Interleukin-10/metabolism , Monocytes/immunology , Mucosal-Associated Invariant T Cells/immunology , SARS-CoV-2/physiology , Adolescent , Adult , Asymptomatic Diseases , Cells, Cultured , Child , Coinfection , Disease Progression , Female , Humans , Immune Tolerance , Lymphocyte Activation , Male , Middle Aged , Severity of Illness Index , Young Adult
20.
J Med Virol ; 93(9): 5438-5445, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1363683

ABSTRACT

Adequate maternal selenium level is essential for immune response and healthy pregnancy. This study aimed to shed light on the selenium status of pregnant women with COVID-19 and the effects of potential deficiency in serum selenium levels. Totally 141 pregnant women, 71 of them were COVID-19 patients, in different trimesters were included in the study. Maternal serum selenium levels, demographic and clinical parameters were determined. Serum selenium levels of pregnant women in the second (p: .0003) and third (p: .001) trimesters with COVID-19 were significantly lower than in the healthy group. Maternal selenium level was found to be negatively correlated with gestational week (p < .0001, r: -.541), D-dimer (p: .0002, r: -.363) and interleukin-6 (IL-6) level (p: .02, r: -.243). In the second trimester, serum selenium level positively correlated with white blood cell (p: .002, r: .424), neutrophil (p: .006, r: .39), lymphocyte (p: .004, r: .410) count and hemoglobin (p: .02, r: .323), hematocrit (p: .008, r: .38) status. In the third trimester, it was found that maternal selenium level positively correlated with monocyte (p: .04, r: .353) and negatively correlated with C-reactive protein level (p: .03, r: -.384). Serum selenium level was gradually decreased during the pregnancy period, however, this natural decrease was enhanced together with COVID-19 infection. The reason might be increased selenium needs depended on the immune response against infection. The decrease in maternal selenium level was found to be related to IL-6 and D-dimer levels, which indicate selenium's role in disease progression.


Subject(s)
COVID-19/blood , COVID-19/immunology , Pregnancy Trimesters/blood , SARS-CoV-2/pathogenicity , Selenium/blood , Adult , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19/virology , Case-Control Studies , Female , Fibrin Fibrinogen Degradation Products/metabolism , Hematocrit , Hemoglobins/metabolism , Humans , Interleukin-6/blood , Lymphocytes/immunology , Lymphocytes/virology , Monocytes/immunology , Monocytes/virology , Neutrophils/immunology , Neutrophils/virology , Pregnancy , Pregnancy Trimesters/immunology , Severity of Illness Index
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