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1.
Biomedica ; 41(Sp. 2): 86-102, 2021 10 15.
Article in English, Spanish | MEDLINE | ID: covidwho-1529016

ABSTRACT

INTRODUCTION: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARSCoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited. OBJECTIVE: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection. MATERIALS AND METHODS: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay. RESULTS: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin. CONCLUSION: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells could be associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.


Subject(s)
COVID-19/immunology , Killer Cells, Natural , SARS-CoV-2/immunology , T-Lymphocytes , Adult , Antibodies, Viral/analysis , CD56 Antigen/immunology , Case-Control Studies , Colombia , Family Health , Granzymes/metabolism , Humans , Interleukin-10/metabolism , Interleukin-1beta/blood , Interleukin-6/blood , Interleukin-8/blood , K562 Cells , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Lymphocyte Activation , Male , Middle Aged , Perforin/metabolism , Phenotype , Receptors, CCR7/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/blood , Young Adult
2.
Crit Rev Immunol ; 41(2): 1-19, 2021.
Article in English | MEDLINE | ID: covidwho-1468219

ABSTRACT

Elucidating the role of probiotic bacteria in health and disease perhaps constitutes one of the most exciting and fastest growing fields in medicine as we uncover the beneficial roles of these bacteria in many disease processes including cancer. We and others have reported previously that probiotic bacteria play a significant role in the activation of many cells including the cancer fighting natural killer (NK) cells. NK cells are the key immune effectors which control tumor growth and metastasis due to their ability to mediate direct cytotoxicity and/or differentiation of cancer stem cells/undifferentiated tumors through secreted and membrane bound interferon-gamma and tumor necrosis factor-alpha. In this review, we present an overview of recent studies from our laboratory and those of the others on their beneficial effects on immune cell function in particular on NK cells. In addition, we also highlight the current understanding of the role of probiotics in enhancement of the effectiveness of cancer therapeutics. Moreover, we discuss the functional impairment of cancer patients' NK cells and the role of probiotics in reversal of such functional impairment. NK cell-based immuno-therapies in combination with well-selected strains of probiotic bacteria may probably represent one of the best adjunct therapeutic approaches to prevent and treat cancer in the future.


Subject(s)
Killer Cells, Natural/cytology , Lymphocyte Activation , Neoplasms , Probiotics , Humans , Neoplasms/therapy , Probiotics/therapeutic use
3.
Br J Haematol ; 195(4): 523-531, 2021 11.
Article in English | MEDLINE | ID: covidwho-1341248

ABSTRACT

Haemato-oncological patients are at risk in case of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Currently, vaccination is the best-evaluated preventive strategy. In the present study, we aimed to assess serological response, predictive markers, and safety of BNT162b2 in haemato-oncological patients. A total of 259 haemato-oncological patients were vaccinated with two 30 µg doses of BNT162b2 administered 21 days apart. Serological response was assessed by ELECSYS® Anti-SARS-CoV-2-S immunoassay before vaccination, and at 3 and 7 weeks after the first dose (T1, T2). Safety assessment was performed. At T2 spike protein receptor binding domain (S/RBD) antibodies were detected in 71·4% of haematological and in 94·5% of oncological patients (P < 0·001). Haematological patients receiving systemic treatment had a 14·2-fold increased risk of non-responding (95% confidence interval 3·2-63·3, P = 0·001). Subgroups of patients with lymphoma or chronic lymphocytic leukaemia were at highest risk of serological non-response. Low immunoglobulin G (IgG) level, lymphocyte- and natural killer (NK)-cell counts were significantly associated with poor serological response (P < 0·05). Vaccination was well tolerated with only 2·7% of patients reporting severe side-effects. Patients with side-effects developed a higher S/RBD-antibody titre compared to patients without side-effects (P = 0·038). Haematological patients under treatment were at highest risk of serological non-response. Low lymphocytes, NK cells and IgG levels were found to be associated with serological non-response. Serological response in oncological patients was encouraging. The use of BNT162b2 is safe in haemato-oncological patients.


Subject(s)
Antibody Formation/drug effects , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Hematologic Neoplasms/immunology , SARS-CoV-2/immunology , Aged , Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19/blood , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Female , Humans , Immunoassay/methods , Immunoglobulin G/blood , Killer Cells, Natural/cytology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Lymphocytes/cytology , Lymphoma/immunology , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , SARS-CoV-2/genetics , Safety
4.
Int J Mol Sci ; 22(13)2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1288903

ABSTRACT

The vulnerability of humankind to SARS-CoV-2 in the absence of a pre-existing immunity, the unpredictability of the infection outcome, and the high transmissibility, broad tissue tropism, and ability to exploit and subvert the immune response pose a major challenge and are likely perpetuating the COVID-19 pandemic. Nevertheless, this peculiar infectious scenario provides researchers with a unique opportunity for studying, with the latest immunological techniques and understandings, the immune response in SARS-CoV-2 naïve versus recovered subjects as well as in SARS-CoV-2 vaccinees. Interestingly, the current understanding of COVID-19 indicates that the combined action of innate immune cells, cytokines, and chemokines fine-tunes the outcome of SARS-CoV-2 infection and the related immunopathogenesis. Indeed, the emerging picture clearly shows that the excessive inflammatory response against this virus is among the main causes of disease severity in COVID-19 patients. In this review, the innate immune response to SARS-CoV-2 infection is described not only in light of its capacity to influence the adaptive immune response towards a protective phenotype but also with the intent to point out the multiple strategies exploited by SARS-CoV-2 to antagonize host antiviral response and, finally, to outline inborn errors predisposing individuals to COVID-19 disease severity.


Subject(s)
COVID-19/pathology , Immunity, Innate , COVID-19/immunology , COVID-19/virology , Chemokines/metabolism , Cytokines/metabolism , Host-Pathogen Interactions , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Monocytes/cytology , Monocytes/metabolism , SARS-CoV-2/isolation & purification , Severity of Illness Index
5.
J Med Virol ; 93(3): 1589-1598, 2021 03.
Article in English | MEDLINE | ID: covidwho-1196482

ABSTRACT

A novel member of human coronavirus, named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been recently recognized in China and rapidly spread worldwide. Studies showed the decreasing of peripheral blood lymphocytes in a majority of patients. In this study, we have reported the clinical features, laboratory characteristics, the frequency of peripheral blood lymphocyte subpopulations, and their apoptosis pattern in Iranian coronavirus infectious disease (COVID-19) patients. Demographic and clinical data of 61 hospitalized confirmed cases with COVID-19 at Imam Khomeini Hospital were collected and analyzed. Peripheral blood mononuclear cells were isolated from all samples and the apoptosis pattern was evaluated using Annexin V/propidium iodide method. The frequency of lymphocyte subsets, including T-CD4+ , T-CD8+ , NK, B cells, and monocytes, was measured in all patients and 31 controls by flow cytometry. Our findings demonstrated that the percentage of lymphocytes, CD4+ , and CD8+ T cells were decreased in COVID-19 patients compared with the control group. Regarding the clinical severity, the number of lymphocytes, CD4+ , CD8+ T cells, and NK cells were also decreased in severe cases when compared with mild cases. Finally, our data have also indicated the increase in apoptosis of mononuclear cells from COVID-19 patients which was more remarkable in severe clinical cases. The frequency of immune cells is a useful indicator for prediction of severity and prognosis of COVID-19 patients. These results could help to explain the immunopathogenesis of SARS-CoV-2 and introducing novel biomarkers, therapeutic strategies, and vaccine candidates.


Subject(s)
B-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Immunophenotyping/methods , Killer Cells, Natural/cytology , SARS-CoV-2/immunology , Adult , Aged , Apoptosis/immunology , Biomarkers/blood , COVID-19/immunology , Female , Flow Cytometry , Humans , Iran , Lymphocyte Count , Lymphopenia/immunology , Male , Middle Aged
6.
BMC Pediatr ; 21(1): 181, 2021 04 17.
Article in English | MEDLINE | ID: covidwho-1190064

ABSTRACT

BACKGROUND: Early diagnostic indicators and the identification of possible progression to severe or critical COVID-19 in children are unknown. To investigate the immune characteristics of early SARS-CoV-2 infection in children and possible key prognostic factors for early identification of critical COVID-19, a retrospective study including 121 children with COVID-19 was conducted. Peripheral blood lymphocyte subset counts, T cell-derived cytokine concentrations, inflammatory factor concentrations, and routine blood counts were analyzed statistically at the initial presentation. RESULTS: The T lymphocyte subset and natural killer cell counts decreased with increasing disease severity. Group III (critical cases) had a higher Th/Tc ratio than groups I and II (common and severe cases); group I had a higher B cell count than groups II and III. IL-6, IL-10, IFN-γ, SAA, and procalcitonin levels increased with increasing disease severity. Hemoglobin concentration, and RBC and eosinophil counts decreased with increasing disease severity. Groups II and III had significantly lower lymphocyte counts than group I. T, Th, Tc, IL-6, IL-10, RBC, and hemoglobin had relatively high contribution and area under the curve values. CONCLUSIONS: Decreased T, Th, Tc, RBC, hemoglobin and increased IL-6 and IL-10 in early SARS-CoV-2 infection in children are valuable indices for early diagnosis of severe disease. The significantly reduced Th and Tc cells and significantly increased IL-6, IL-10, ferritin, procalcitonin, and SAA at this stage in children with critical COVID-19 may be closely associated with the systemic cytokine storm caused by immune dysregulation.


Subject(s)
COVID-19/diagnosis , Systemic Inflammatory Response Syndrome/diagnosis , Adolescent , B-Lymphocytes/cytology , Child , Child, Preschool , Cytokine Release Syndrome/virology , Cytokines/blood , Female , Humans , Immunity , Infant , Killer Cells, Natural/cytology , Lymphocyte Count , Male , Prognosis , Retrospective Studies , Severity of Illness Index , T-Lymphocyte Subsets/cytology
7.
Front Immunol ; 11: 580237, 2020.
Article in English | MEDLINE | ID: covidwho-1116681

ABSTRACT

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) induced Coronavirus Disease 2019 (COVID-19) has posed a global threat to public health. The immune system is crucial in defending and eliminating the virus and infected cells. However, immune dysregulation may result in the rapid progression of COVID-19. Here, we evaluated the subsets, phenotypic and functional characteristics of natural killer (NK) and T cells in patients with COVID-19 and their associations with disease severity. Methods: Demographic and clinical data of COVID-19 patients enrolled in Wuhan Union Hospital from February 25 to February 27, 2020, were collected and analyzed. The phenotypic and functional characteristics of NK cells and T cells subsets in circulating blood and serum levels of cytokines were analyzed via flow cytometry. Then the LASSO logistic regression model was employed to predict risk factors for the severity of COVID-19. Results: The counts and percentages of NK cells, CD4+ T cells, CD8+ T cells and NKT cells were significantly reduced in patients with severe symptoms. The cytotoxic CD3-CD56dimCD16+ cell population significantly decreased, while the CD3-CD56dimCD16- part significantly increased in severe COVID-19 patients. More importantly, elevated expression of regulatory molecules, such as CD244 and programmed death-1 (PD-1), on NK cells and T cells, as well as decreased serum cytotoxic effector molecules including perforin and granzyme A, were detected in patients with COVID-19. The serum IL-6, IL-10, and TNF-α were significantly increased in severe patients. Moreover, the CD3-CD56dimCD16- cells were screened out as an influential factor in severe cases by LASSO logistic regression. Conclusions: The functional exhaustion and other subset alteration of NK and T cells may contribute to the progression and improve the prognosis of COVID-19. Surveillance of lymphocyte subsets may in the future enable early screening for signs of critical illness and understanding the pathogenesis of this disease.


Subject(s)
CD8-Positive T-Lymphocytes/cytology , COVID-19/blood , Killer Cells, Natural/cytology , SARS-CoV-2/physiology , Adult , Aged , CD8-Positive T-Lymphocytes/immunology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , China/epidemiology , Female , Flow Cytometry , Humans , Killer Cells, Natural/immunology , Leukocyte Count , Male , Middle Aged , Pandemics , Prognosis , SARS-CoV-2/genetics , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology
8.
Cell ; 184(7): 1836-1857.e22, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1077815

ABSTRACT

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.


Subject(s)
COVID-19/immunology , Cytokines/metabolism , Dendritic Cells/metabolism , Gene Expression/immunology , Killer Cells, Natural/metabolism , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , COVID-19/mortality , Case-Control Studies , Dendritic Cells/cytology , Female , Humans , Killer Cells, Natural/cytology , Longitudinal Studies , Male , Middle Aged , Transcriptome/immunology , Young Adult
9.
Am J Physiol Lung Cell Mol Physiol ; 320(1): L84-L98, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-910283

ABSTRACT

Coronavirus disease 2019 (COVID-19), driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic in March 2020. Pathogenic T cells and inflammatory monocytes are regarded as the central drivers of the cytokine storm associated with the severity of COVID-19. In this study, we explored the characteristic peripheral cellular profiles of patients with COVID-19 in both acute and convalescent phases by single-cell mass cytometry (CyTOF). Using a combination of algorithm-guided data analyses, we identified peripheral immune cell subsets in COVID-19 and revealed CD4+ T-cell depletion, T-cell differentiation, plasma cell expansion, and the reduced antigen presentation capacity of innate immunity. Notably, COVID-19 induces a dysregulation in the balance of monocyte populations by the expansion of the monocyte subsets. Collectively, our results represent a high-dimensional, single-cell profile of the peripheral immune response to SARS-CoV-2 infection.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , Leukocytes, Mononuclear/immunology , Monocytes/immunology , SARS-CoV-2/immunology , Adult , Aged , Antigen Presentation/immunology , CD4-Positive T-Lymphocytes/cytology , COVID-19/pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokines/immunology , Dendritic Cells/cytology , Dendritic Cells/immunology , Female , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Leukocytes, Mononuclear/cytology , Lymphocyte Depletion , Male , Middle Aged , Monocytes/cytology , Plasma Cells/cytology , Single-Cell Analysis
10.
Sci Rep ; 10(1): 17718, 2020 10 19.
Article in English | MEDLINE | ID: covidwho-880700

ABSTRACT

COVID-19 has been widely spreading. We aimed to examine adaptive immune cells in non-severe patients with persistent SARS-CoV-2 shedding. 37 non-severe patients with persistent SARS-CoV-2 presence that were transferred to Zhongnan hospital of Wuhan University were retrospectively recruited to the PP (persistently positive) group, which was further allocated to PPP group (n = 19) and PPN group (n = 18), according to their testing results after 7 days (N = negative). Epidemiological, demographic, clinical and laboratory data were collected and analyzed. Data from age- and sex-matched non-severe patients at disease onset (PA [positive on admission] patients, n = 37), and lymphocyte subpopulation measurements from matched 54 healthy subjects were extracted for comparison (HC). Compared with PA patients, PP patients had much improved laboratory findings. The absolute numbers of CD3+ T cells, CD4+ T cells, and NK cells were significantly higher in PP group than that in PA group, and were comparable to that in healthy controls. PPP subgroup had markedly reduced B cells and T cells compared to PPN group and healthy subjects. Finally, paired results of these lymphocyte subpopulations from 10 PPN patients demonstrated that the number of T cells and B cells significantly increased when the SARS-CoV-2 tests turned negative. Persistent SARS-CoV-2 presence in non-severe COVID-19 patients is associated with reduced numbers of adaptive immune cells. Monitoring lymphocyte subpopulations could be clinically meaningful in identifying fully recovered COVID-19 patients.


Subject(s)
B-Lymphocytes/cytology , Coronavirus Infections/pathology , Pneumonia, Viral/pathology , T-Lymphocytes/cytology , Adult , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Betacoronavirus/isolation & purification , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , COVID-19 , Case-Control Studies , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
11.
Cell ; 183(4): 982-995.e14, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-756809

ABSTRACT

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution.


Subject(s)
Inflammation/pathology , Systemic Inflammatory Response Syndrome/pathology , Adolescent , Antibodies, Viral/blood , Autoantibodies/blood , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , COVID-19 , Chemokine CCL3/metabolism , Child , Child, Preschool , Coronavirus Infections/complications , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Immunity, Humoral , Infant , Infant, Newborn , Inflammation/metabolism , Interleukin-17/metabolism , Interleukin-18/metabolism , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Young Adult
12.
Cytometry A ; 97(8): 772-776, 2020 08.
Article in English | MEDLINE | ID: covidwho-600033

ABSTRACT

A reduced peripheral blood absolute lymphocyte count with an elevated neutrophil count has been a consistent observation in hospitalized coronavirus disease 2019 (COVID-19) patients. In this brief meta-analysis, the reduction of lymphocyte subset counts in COVID-19 patients was investigated across 20 peer-reviewed studies meeting criteria for reporting lymphocyte subset counts and COVID-19 disease severity. CD4+ T cell, CD8+ T cell, B cell, NK cell, and total lymphocyte cell counts all showed statistically significant reduction in patients with severe/critical COVID-19 disease compared to mild/moderate disease. T-cell subsets showed the largest standardized magnitude of change. In some studies, multivariate analysis has shown that CD4 and/or CD8 T-cells counts are independently predictive of patient outcomes. © 2020 International Society for Advancement of Cytometry.


Subject(s)
B-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Coronavirus Infections/blood , Killer Cells, Natural/cytology , Pneumonia, Viral/blood , T-Lymphocyte Subsets/cytology , Betacoronavirus , COVID-19 , Humans , Lymphocyte Count , Neutrophils/cytology , Pandemics , SARS-CoV-2
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