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1.
Theranostics ; 12(1): 290-306, 2022.
Article in English | MEDLINE | ID: covidwho-1579955

ABSTRACT

Coronavirus disease 2019 (COVID19), caused by SARS-CoV-2, is a complex disease, with a variety of clinical manifestations ranging from asymptomatic infection or mild cold-like symptoms to more severe cases requiring hospitalization and critical care. The most severe presentations seem to be related with a delayed, deregulated immune response leading to exacerbated inflammation and organ damage with close similarities to sepsis. Methods: In order to improve the understanding on the relation between host immune response and disease course, we have studied the differences in the cellular (monocytes, CD8+ T and NK cells) and soluble (cytokines, chemokines and immunoregulatory ligands) immune response in blood between Healthy Donors (HD), COVID19 and a group of patients with non-COVID19 respiratory tract infections (NON-COV-RTI). In addition, the immune response profile has been analyzed in COVID19 patients according to disease severity. Results: In comparison to HDs and patients with NON-COV-RTI, COVID19 patients show a heterogeneous immune response with the presence of both activated and exhausted CD8+ T and NK cells characterised by the expression of the immune checkpoint LAG3 and the presence of the adaptive NK cell subset. An increased frequency of adaptive NK cells and a reduction of NK cells expressing the activating receptors NKp30 and NKp46 correlated with disease severity. Although both activated and exhausted NK cells expressing LAG3 were increased in moderate/severe cases, unsupervised cell clustering analyses revealed a more complex scenario with single NK cells expressing more than one immune checkpoint (PD1, TIM3 and/or LAG3). A general increased level of inflammatory cytokines and chemokines was found in COVID19 patients, some of which like IL18, IL1RA, IL36B and IL31, IL2, IFNα and TNFα, CXCL10, CCL2 and CCL8 were able to differentiate between COVID19 and NON-COV-RTI and correlated with bad prognosis (IL2, TNFα, IL1RA, CCL2, CXCL10 and CXCL9). Notably, we found that soluble NKG2D ligands from the MIC and ULBPs families were increased in COVID19 compared to NON-COV-RTI and correlated with disease severity. Conclusions: Our results provide a detailed comprehensive analysis of the presence of activated and exhausted CD8+T, NK and monocyte cell subsets as well as extracellular inflammatory factors beyond cytokines/chemokines, specifically associated to COVID19. Importantly, multivariate analysis including clinical, demographical and immunological experimental variables have allowed us to reveal specific immune signatures to i) differentiate COVID19 from other infections and ii) predict disease severity and the risk of death.


Subject(s)
COVID-19/blood , COVID-19/immunology , Adult , Aged , Aged, 80 and over , Biomarkers/blood , CD8-Positive T-Lymphocytes/virology , COVID-19/mortality , Case-Control Studies , Chemokines/blood , Cytokines/blood , Female , Hospitalization , Humans , Killer Cells, Natural/virology , Logistic Models , Male , Middle Aged , Monocytes/virology , Prospective Studies , Respiratory Tract Infections/blood , Respiratory Tract Infections/immunology , Severity of Illness Index
2.
Sci Rep ; 11(1): 21514, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1500512

ABSTRACT

Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation. A wide range of adipokines activities suggests they influence pathogenesis and infection course. The aim was to assess concentrations of chemerin, omentin, and vaspin among COVID-19 patients with an emphasis on adipokines relationship with COVID-19 severity, concomitant metabolic abnormalities and liver dysfunction. Serum chemerin, omentin and vaspin concentrations were measured in serum collected from 70 COVID-19 patients at the moment of admission to hospital, before any treatment was applied and 20 healthy controls. Serum chemerin and omentin concentrations were significantly decreased in COVID-19 patients compared to healthy volunteers (271.0 vs. 373.0 ng/ml; p < 0.001 and 482.1 vs. 814.3 ng/ml; p = 0.01, respectively). There were no correlations of analyzed adipokines with COVID-19 severity based on the presence of pneumonia, dyspnea, or necessity of Intensive Care Unit hospitalization (ICU). Liver test abnormalities did not influence adipokines levels. Elevated GGT activity was associated with ICU admission, presence of pneumonia and elevated concentrations of CRP, ferritin and interleukin 6. Chemerin and omentin depletion in COVID-19 patients suggests that this adipokines deficiency play influential role in disease pathogenesis. However, there was no relationship between lower adipokines level and frequency of COVID-19 symptoms as well as disease severity. The only predictive factor which could predispose to a more severe COVID-19 course, including the presence of pneumonia and ICU hospitalization, was GGT activity.


Subject(s)
Adipokines/blood , Chemokines/blood , Cytokines/blood , Lectins/blood , Serpins/blood , Aged , Body Mass Index , C-Reactive Protein/analysis , COVID-19/complications , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Female , GPI-Linked Proteins/blood , Hospitalization , Humans , Liver/metabolism , Male , Metabolic Syndrome/complications , Middle Aged , SARS-CoV-2/isolation & purification , gamma-Glutamyltransferase/metabolism
3.
Front Immunol ; 12: 752397, 2021.
Article in English | MEDLINE | ID: covidwho-1497081

ABSTRACT

Covaxin/BBV152 is a whole virion inactivated SARS-CoV-2 vaccine. The effect of prime-boost vaccination with Covaxin on systemic immune responses is not known. We investigated the effect of Covaxin on the plasma levels of a wide panel of cytokines and chemokines at baseline (M0) and at months 1 (M1), 2 (M2) and 3 (M3) following prime-boost vaccination in healthy volunteers. Our results demonstrate that Covaxin induces enhanced plasma levels of Type 1 cytokines (IFNγ, IL-2, TNFα), Type 2/regulatory cytokines (IL-4, IL-5, IL-10 and IL-13), Type 17 cytokine (IL-17A), other pro-inflammatory cytokines (IL-6, IL-12, IL-1α, IL-1ß) and other cytokines (IL-3 and IL-7) but diminished plasma levels of IL-25, IL-33, GM-CSF and Type 1 IFNs. Covaxin also induced enhanced plasma levels of CC chemokine (CCL4) and CXC chemokines (CXCL1, CXCL2 and CX3CL1) but diminished levels of CXCL10. Covaxin vaccination induces enhanced cytokine and chemokine responses as early as month 1, following prime-boost vaccination, indicating robust activation of innate and adaptive immune responses in vaccine recipients.


Subject(s)
COVID-19 Vaccines/immunology , SARS-CoV-2/physiology , Vaccines, Inactivated/immunology , Adaptive Immunity , Adult , Chemokines/blood , Cytokines/blood , Female , Healthy Volunteers , Humans , Immunity, Innate , Immunization , Immunization, Secondary , Male , Middle Aged , Vaccination , Young Adult
4.
PLoS Pathog ; 17(10): e1010025, 2021 10.
Article in English | MEDLINE | ID: covidwho-1496544

ABSTRACT

The global SARS-CoV-2 coronavirus pandemic continues to be devastating in many areas. Treatment options have been limited and convalescent donor plasma has been used by many centers to transfer passive neutralizing antibodies to patients with respiratory involvement. The results often vary by institution and are complicated by the nature and quality of the donor plasma itself, the timing of administration and the clinical aspects of the recipients. SARS-CoV-2 infection is known to be associated with an increase in the blood concentrations of several inflammatory cytokines/chemokines, as part of the overall immune response to the virus and consequential to mediated lung pathology. Some of these correlates contribute to the cytokine storm syndrome and acute respiratory distress syndrome, often resulting in fatality. A Phase IIa clinical trial at our institution using high neutralizing titer convalescent plasma transfer gave us the unique opportunity to study the elevations of correlates in the first 10 days after infusion. Plasma recipients were divided into hospitalized COVID-19 pneumonia patients who did not (Track 2) or did (Track 3) require mechanical ventilation. Several cytokines were elevated in the patients of each Track and some continued to rise through Day 10, while others initially increased and then subsided. Furthermore, elevations in MIP-1α, MIP-1ß and CRP correlated with disease progression of Track 2 recipients. Overall, our observations serve as a foundation for further study of these correlates and the identification of potential biomarkers to improve upon convalescent plasma therapy and to drive more successful patient outcomes.


Subject(s)
COVID-19/therapy , Chemokines/blood , Cytokines/blood , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , COVID-19/immunology , Female , Humans , Immunization, Passive , Immunoglobulin Isotypes/blood , Male , Middle Aged
5.
Hamostaseologie ; 41(5): 379-385, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1483188

ABSTRACT

In 2019 first reports about a new human coronavirus emerged, which causes common cold symptoms as well as acute respiratory distress syndrome. The virus was identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and severe thrombotic events including deep vein thrombosis, pulmonary embolism, and microthrombi emerged as additional symptoms. Heart failure, myocardial infarction, myocarditis, and stroke have also been observed. As main mediator of thrombus formation, platelets became one of the key aspects in SARS-CoV-2 research. Platelets may also directly interact with SARS-CoV-2 and have been shown to carry the SARS-CoV-2 virus. Platelets can also facilitate the virus uptake by secretion of the subtilisin-like proprotein convertase furin. Cleavage of the SARS-CoV-2 spike protein by furin enhances binding capabilities and virus entry into various cell types. In COVID-19 patients, platelet count differs between mild and serious infections. Patients with mild symptoms have a slightly increased platelet count, whereas thrombocytopenia is a hallmark of severe COVID-19 infections. Low platelet count can be attributed to platelet apoptosis and the incorporation of platelets into microthrombi (peripheral consumption) and severe thrombotic events. The observed excessive formation of thrombi is due to hyperactivation of platelets caused by the infection. Various factors have been suggested in the activation of platelets in COVID-19, such as hypoxia, vessel damage, inflammatory factors, NETosis, SARS-CoV-2 interaction, autoimmune reactions, and autocrine activation. COVID-19 does alter chemokine and cytokine plasma concentrations. Platelet chemokine profiles are altered in COVID-19 and contribute to the described chemokine storms observed in severely ill COVID-19 patients.


Subject(s)
Blood Platelets/physiology , Blood Platelets/virology , COVID-19/blood , Blood Platelets/immunology , COVID-19/complications , COVID-19/immunology , Chemokines/blood , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Host Microbial Interactions/immunology , Host Microbial Interactions/physiology , Humans , Models, Biological , Pandemics , Platelet Activation/immunology , Platelet Activation/physiology , SARS-CoV-2/pathogenicity , Thrombosis/blood , Thrombosis/etiology
6.
J Med Virol ; 93(10): 5805-5815, 2021 10.
Article in English | MEDLINE | ID: covidwho-1453606

ABSTRACT

Aggressive immune response, due to overexpressed proinflammatory molecules, has been characterized in coronavirus disease 2019 (COVID-19) patients. Some of those mediators have a dual and opposite role on immune systems at play behind differential disease severities. We investigated the expression of some cytokines and chemokines in COVID-19 patients in Bangladesh. We diagnosed the patients by detecting severe acute respiratory syndrome coronavirus 2 RNA in nasal swab samples by the real-time RT-PCR method. Thirty adult patients were preselected based on their disease severities and grouped into mild, moderate, and severe cases. Nine healthy volunteers participated in this study as a control. Relative expression of nine cytokines/chemokine in total leukocytes was semi-quantified in SYBRgreen-based real-time quantitative reverse-transcriptase polymerase chain reaction. We performed statistical tests on transformed log data using SPSS 24.0. At the onset of symptoms (Day 1), angiotensin-converting enzyme 2 (ACE2) (p < 0.05) and interleukin (IL)-6 (p > 0.05) were upregulated in all COVID-19 groups, although the expression levels did not significantly correlate with disease severities. However, expressions of IL-6, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, tumor necrosis factor-α (TNF-α), RANTES (regulated upon activation, normal T cell expressed and secreted), and ACE2, on Day 14, were positively correlated with disease severities. Relative viral load at Day 1 showed no significant correlation with cytokine expression but had a significant positive correlation with RANTES and ACE2 expression on Day 14 (p < 0.05). Male patients had a higher level of IL-6 than female patients on Day 1 (p < 0.05). All COVID-19 patients showed upregulated cytokines and chemokines on Day 14 compared to Day 1 except TNF-α. Female patients had a higher expression of ACE2 and IL-12 on Day 14. Upregulated cytokines/chemokines at the convalescent stage, especially IL-6, may help in targeting anticytokine therapy in post-COVID-19 patients' management.


Subject(s)
COVID-19/diagnosis , Cytokines/blood , Adult , Bangladesh/epidemiology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Chemokines/blood , Female , Humans , Male , Middle Aged , SARS-CoV-2/isolation & purification , Severity of Illness Index , Viral Load
7.
Front Immunol ; 12: 681516, 2021.
Article in English | MEDLINE | ID: covidwho-1399136

ABSTRACT

Coronavirus disease 2019 (COVID-19) broke out and then became a global epidemic at the end of 2019. With the increasing number of deaths, early identification of disease severity and interpretation of pathogenesis are very important. Aiming to identify biomarkers for disease severity and progression of COVID-19, 75 COVID-19 patients, 34 healthy controls and 23 patients with pandemic influenza A(H1N1) were recruited in this study. Using liquid chip technology, 48 cytokines and chemokines were examined, among which 33 were significantly elevated in COVID-19 patients compared with healthy controls. HGF and IL-1ß were strongly associated with APACHE II score in the first week after disease onset. IP-10, HGF and IL-10 were correlated positively with virus titers. Cytokines were significantly correlated with creatinine, troponin I, international normalized ratio and procalcitonin within two weeks after disease onset. Univariate analyses were carried out, and 6 cytokines including G-CSF, HGF, IL-10, IL-18, M-CSF and SCGF-ß were found to be associated with the severity of COVID-19. 11 kinds of cytokines could predict the severity of COVID-19, among which IP-10 and M-CSF were excellent predictors for disease severity. In conclusion, the levels of cytokines in COVID-19 were significantly correlated with the severity of the disease in the early stage, and serum cytokines could be used as warning indicators of the severity and progression of COVID-19. Early stratification of disease and intervention to reduce hypercytokinaemia may improve the prognosis of COVID-19 patients.


Subject(s)
COVID-19/immunology , Cytokines/genetics , Cytokines/immunology , SARS-CoV-2/immunology , Severity of Illness Index , Transcriptome/immunology , Adult , Aged , Biomarkers/blood , Chemokines/blood , Chemokines/genetics , Chemokines/immunology , Cytokines/blood , Female , Hospitalization/statistics & numerical data , Humans , Influenza, Human/blood , Influenza, Human/immunology , Male , Middle Aged
8.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1381012

ABSTRACT

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.


Subject(s)
COVID-19/immunology , Interferon Type I/immunology , Interferon-gamma/immunology , Interferons/immunology , COVID-19/blood , Chemokines/blood , Cytokines/blood , Humans , Interferon Type I/blood , Interferon Type I/genetics , Interferon-gamma/blood , Interferon-gamma/genetics , Interferons/blood , Leukocytes, Mononuclear/immunology , SARS-CoV-2/isolation & purification
9.
PLoS One ; 16(8): e0256784, 2021.
Article in English | MEDLINE | ID: covidwho-1378138

ABSTRACT

Viral sepsis has been proposed as an accurate term to describe all multisystemic dysregulations and clinical findings in severe and critically ill COVID-19 patients. The adoption of this term may help the implementation of more accurate strategies of early diagnosis, prognosis, and in-hospital treatment. We accurately quantified 110 metabolites using targeted metabolomics, and 13 cytokines/chemokines in plasma samples of 121 COVID-19 patients with different levels of severity, and 37 non-COVID-19 individuals. Analyses revealed an integrated host-dependent dysregulation of inflammatory cytokines, neutrophil activation chemokines, glycolysis, mitochondrial metabolism, amino acid metabolism, polyamine synthesis, and lipid metabolism typical of sepsis processes distinctive of a mild disease. Dysregulated metabolites and cytokines/chemokines showed differential correlation patterns in mild and critically ill patients, indicating a crosstalk between metabolism and hyperinflammation. Using multivariate analysis, powerful models for diagnosis and prognosis of COVID-19 induced sepsis were generated, as well as for mortality prediction among septic patients. A metabolite panel made of kynurenine/tryptophan ratio, IL-6, LysoPC a C18:2, and phenylalanine discriminated non-COVID-19 from sepsis patients with an area under the curve (AUC (95%CI)) of 0.991 (0.986-0.995), with sensitivity of 0.978 (0.963-0.992) and specificity of 0.920 (0.890-0.949). The panel that included C10:2, IL-6, NLR, and C5 discriminated mild patients from sepsis patients with an AUC (95%CI) of 0.965 (0.952-0.977), with sensitivity of 0.993(0.984-1.000) and specificity of 0.851 (0.815-0.887). The panel with citric acid, LysoPC a C28:1, neutrophil-lymphocyte ratio (NLR) and kynurenine/tryptophan ratio discriminated severe patients from sepsis patients with an AUC (95%CI) of 0.829 (0.800-0.858), with sensitivity of 0.738 (0.695-0.781) and specificity of 0.781 (0.735-0.827). Septic patients who survived were different from those that did not survive with a model consisting of hippuric acid, along with the presence of Type II diabetes, with an AUC (95%CI) of 0.831 (0.788-0.874), with sensitivity of 0.765 (0.697-0.832) and specificity of 0.817 (0.770-0.865).


Subject(s)
COVID-19/pathology , Metabolomics , Sepsis/diagnosis , Adult , Area Under Curve , COVID-19/complications , COVID-19/virology , Chemokines/blood , Cytokines/blood , Female , Humans , Kynurenine/blood , Lymphocytes/cytology , Male , Middle Aged , Neutrophils/cytology , ROC Curve , Retrospective Studies , Risk Factors , SARS-CoV-2/isolation & purification , Sepsis/etiology , Severity of Illness Index , Tryptophan/blood
10.
Nature ; 588(7837): 315-320, 2020 12.
Article in English | MEDLINE | ID: covidwho-1337122

ABSTRACT

There is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women1-5. However, whether immune responses against severe acute respiratory syndrome coronavirus (SARS-CoV-2) differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID-19, is currently unknown. Here we examined sex differences in viral loads, SARS-CoV-2-specific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID-19 who had not received immunomodulatory medications. Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. By contrast, female patients had more robust T cell activation than male patients during SARS-CoV-2 infection. Notably, we found that a poor T cell response negatively correlated with patients' age and was associated with worse disease outcome in male patients, but not in female patients. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19.


Subject(s)
COVID-19/immunology , Cytokines/immunology , Immunity, Innate/immunology , SARS-CoV-2/immunology , Sex Characteristics , T-Lymphocytes/immunology , COVID-19/blood , COVID-19/virology , Chemokines/blood , Chemokines/immunology , Cohort Studies , Cytokines/blood , Disease Progression , Female , Humans , Lymphocyte Activation , Male , Monocytes/immunology , Phenotype , Prognosis , RNA, Viral/analysis , SARS-CoV-2/pathogenicity , Viral Load
11.
Life Sci Alliance ; 4(9)2021 09.
Article in English | MEDLINE | ID: covidwho-1332524

ABSTRACT

The use of high-dose of intravenous immunoglobulins (IVIGs) as immunomodulators for the treatment of COVID-19-affected individuals has shown promising results. IVIG reduced inflammation in these patients, who progressively restored respiratory function. However, little is known about how they may modulate immune responses in COVID-19 individuals. Here, we have analyzed the levels of 41 inflammatory biomarkers in plasma samples obtained at day 0 (pretreatment initiation), 3, 7, and 14 from five hospitalized COVID-19 patients treated with a 5-d course of 400 mg/kg/d of IVIG. The plasmatic levels of several cytokines (Tumor Necrosis Factor, IL-10, IL-5, and IL-7), chemokines (macrophage inflammatory protein-1α), growth/tissue repairing factors (hepatic growth factor), complement activation (C5a), and intestinal damage such as Fatty acid-binding protein 2 and LPS-binding protein showed a progressive decreasing trend during the next 2 wk after treatment initiation. This trend was not observed in IVIG-untreated COVID-19 patients. Thus, the administration of high-dose IVIG to hospitalized COVID-19 patients may improve their clinical evolution by modulating their hyperinflammatory and immunosuppressive status.


Subject(s)
COVID-19/therapy , Immunoglobulins, Intravenous/therapeutic use , Administration, Intravenous , Adult , Aged , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Chemokines/blood , Cytokines/blood , Female , Humans , Immunity/immunology , Immunoglobulins/immunology , Immunoglobulins/therapeutic use , Immunoglobulins, Intravenous/immunology , Inflammation/blood , Inflammation/therapy , Inflammation/virology , Male , Middle Aged , SARS-CoV-2/isolation & purification
12.
Front Immunol ; 12: 668725, 2021.
Article in English | MEDLINE | ID: covidwho-1317223

ABSTRACT

COVID-19 severity due to innate immunity dysregulation accounts for prolonged hospitalization, critical complications, and mortality. Severe SARS-CoV-2 infections involve the complement pathway activation for cytokine storm development. Nevertheless, the role of complement in COVID-19 immunopathology, complement-modulating treatment strategies against COVID-19, and the complement and SARS-CoV-2 interaction with clinical disease outcomes remain elusive. This study investigated the potential changes in complement signaling, and the associated inflammatory mediators, in mild-to-critical COVID-19 patients and their clinical outcomes. A total of 53 patients infected with SARS-CoV-2 were enrolled in the study (26 critical and 27 mild cases), and additional 18 healthy control patients were also included. Complement proteins and inflammatory cytokines and chemokines were measured in the sera of patients with COVID-19 as well as healthy controls by specific enzyme-linked immunosorbent assay. C3a, C5a, and factor P (properdin), as well as interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, and IgM antibody levels, were higher in critical COVID-19 patients compared to mild COVID-19 patients. Additionally, compared to the mild COVID-19 patients, factor I and C4-BP levels were significantly decreased in the critical COVID-19 patients. Meanwhile, RANTES levels were significantly higher in the mild patients compared to critical patients. Furthermore, the critical COVID-19 intra-group analysis showed significantly higher C5a, C3a, and factor P levels in the critical COVID-19 non-survival group than in the survival group. Additionally, IL-1ß, IL-6, and IL-8 were significantly upregulated in the critical COVID-19 non-survival group compared to the survival group. Finally, C5a, C3a, factor P, and serum IL-1ß, IL-6, and IL-8 levels positively correlated with critical COVID-19 in-hospital deaths. These findings highlight the potential prognostic utility of the complement system for predicting COVID-19 severity and mortality while suggesting that complement anaphylatoxins and inflammatory cytokines are potential treatment targets against COVID-19.


Subject(s)
Anaphylatoxins/analysis , COVID-19/blood , COVID-19/mortality , Chemokines/blood , Hospital Mortality , SARS-CoV-2/genetics , Severity of Illness Index , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/virology , Case-Control Studies , Cytokine Release Syndrome , Female , Humans , Male , Middle Aged , Prognosis , Young Adult
13.
PLoS One ; 16(7): e0254367, 2021.
Article in English | MEDLINE | ID: covidwho-1304472

ABSTRACT

COVID-19 serological test must have high sensitivity as well as specificity to rule out cross-reactivity with common coronaviruses (HCoVs). We have developed a quantitative multiplex test, measuring antibodies against spike (S) proteins of SARS-CoV-2, SARS-CoV, MERS-CoV, and common human coronavirus strains (229E, NL63, OC43, HKU1), and nucleocapsid (N) protein of SARS-CoV viruses. Receptor binding domain of S protein of SARS-CoV-2 (S-RBD), and N protein, demonstrated sensitivity (94% and 92.5%, respectively) in COVID-19 patients (n = 53), with 98% specificity in non-COVID-19 respiratory-disease (n = 98), and healthy-controls (n = 129). Anti S-RBD and N antibodies appeared five to ten days post-onset of symptoms, peaking at approximately four weeks. The appearance of IgG and IgM coincided while IgG subtypes, IgG1 and IgG3 appeared soon after the total IgG; IgG2 and IgG4 remained undetectable. Several inflammatory cytokines/chemokines were found to be elevated in many COVID-19 patients (e.g., Eotaxin, Gro-α, CXCL-10 (IP-10), RANTES (CCL5), IL-2Rα, MCP-1, and SCGF-b); CXCL-10 was elevated in all. In contrast to antibody titers, levels of CXCL-10 decreased with the improvement in patient health suggesting it as a candidate for disease resolution. Importantly, anti-N antibodies appear before S-RBD and differentiate between vaccinated and infected people-current vaccines (and several in the pipeline) are S protein-based.


Subject(s)
Antibodies, Viral , COVID-19 , Chemokines , Coronavirus Nucleocapsid Proteins , Immunoglobulin G , Immunoglobulin M , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Adult , Animals , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/immunology , Chemokines/blood , Chemokines/immunology , Coronavirus Nucleocapsid Proteins/blood , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Macaca mulatta , Male , Middle Aged , Phosphoproteins/blood , Phosphoproteins/immunology , Rabbits , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/blood , Spike Glycoprotein, Coronavirus/immunology
14.
PLoS One ; 16(6): e0253487, 2021.
Article in English | MEDLINE | ID: covidwho-1280634

ABSTRACT

Although SARS-CoV-2-neutralizing antibodies are promising therapeutics against COVID-19, little is known about their mechanism(s) of action or effective dosing windows. We report the generation and development of SC31, a potent SARS-CoV-2 neutralizing antibody, isolated from a convalescent patient. Antibody-mediated neutralization occurs via an epitope within the receptor-binding domain of the SARS-CoV-2 Spike protein. SC31 exhibited potent anti-SARS-CoV-2 activities in multiple animal models. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, treatment with SC31 greatly reduced viral loads and attenuated pro-inflammatory responses linked to the severity of COVID-19. Importantly, a comparison of the efficacies of SC31 and its Fc-null LALA variant revealed that the optimal therapeutic efficacy of SC31 requires Fc-mediated effector functions that promote IFNγ-driven anti-viral immune responses, in addition to its neutralization ability. A dose-dependent efficacy of SC31 was observed down to 5mg/kg when administered before viral-induced lung inflammatory responses. In addition, antibody-dependent enhancement was not observed even when infected mice were treated with SC31 at sub-therapeutic doses. In SARS-CoV-2-infected hamsters, SC31 treatment significantly prevented weight loss, reduced viral loads, and attenuated the histopathology of the lungs. In rhesus macaques, the therapeutic potential of SC31 was evidenced through the reduction of viral loads in both upper and lower respiratory tracts to undetectable levels. Together, the results of our preclinical studies demonstrated the therapeutic efficacy of SC31 in three different models and its potential as a COVID-19 therapeutic candidate.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , COVID-19/therapy , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Neutralizing/metabolism , COVID-19/immunology , COVID-19/virology , Chemokines/blood , Chemokines/genetics , Chlorocebus aethiops , Convalescence , Cricetinae , Cytokines/blood , Cytokines/genetics , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Humans , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/immunology , Immunoglobulin G/isolation & purification , Macaca mulatta , Male , Mice, Transgenic , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Viral Load
15.
J Med Virol ; 93(10): 5805-5815, 2021 10.
Article in English | MEDLINE | ID: covidwho-1267464

ABSTRACT

Aggressive immune response, due to overexpressed proinflammatory molecules, has been characterized in coronavirus disease 2019 (COVID-19) patients. Some of those mediators have a dual and opposite role on immune systems at play behind differential disease severities. We investigated the expression of some cytokines and chemokines in COVID-19 patients in Bangladesh. We diagnosed the patients by detecting severe acute respiratory syndrome coronavirus 2 RNA in nasal swab samples by the real-time RT-PCR method. Thirty adult patients were preselected based on their disease severities and grouped into mild, moderate, and severe cases. Nine healthy volunteers participated in this study as a control. Relative expression of nine cytokines/chemokine in total leukocytes was semi-quantified in SYBRgreen-based real-time quantitative reverse-transcriptase polymerase chain reaction. We performed statistical tests on transformed log data using SPSS 24.0. At the onset of symptoms (Day 1), angiotensin-converting enzyme 2 (ACE2) (p < 0.05) and interleukin (IL)-6 (p > 0.05) were upregulated in all COVID-19 groups, although the expression levels did not significantly correlate with disease severities. However, expressions of IL-6, monocyte chemotactic protein-1, macrophage inflammatory protein-1α, tumor necrosis factor-α (TNF-α), RANTES (regulated upon activation, normal T cell expressed and secreted), and ACE2, on Day 14, were positively correlated with disease severities. Relative viral load at Day 1 showed no significant correlation with cytokine expression but had a significant positive correlation with RANTES and ACE2 expression on Day 14 (p < 0.05). Male patients had a higher level of IL-6 than female patients on Day 1 (p < 0.05). All COVID-19 patients showed upregulated cytokines and chemokines on Day 14 compared to Day 1 except TNF-α. Female patients had a higher expression of ACE2 and IL-12 on Day 14. Upregulated cytokines/chemokines at the convalescent stage, especially IL-6, may help in targeting anticytokine therapy in post-COVID-19 patients' management.


Subject(s)
COVID-19/diagnosis , Cytokines/blood , Adult , Bangladesh/epidemiology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Chemokines/blood , Female , Humans , Male , Middle Aged , SARS-CoV-2/isolation & purification , Severity of Illness Index , Viral Load
16.
PLoS One ; 16(5): e0252026, 2021.
Article in English | MEDLINE | ID: covidwho-1243847

ABSTRACT

To investigate the mechanisms underlying the SARS-CoV-2 infection severity observed in patients with obesity, we performed a prospective study of 51 patients evaluating the impact of multiple immune parameters during 2 weeks after admission, on vital organs' functions according to body mass index (BMI) categories. High-dimensional flow cytometric characterization of immune cell subsets was performed at admission, 30 systemic cytokines/chemokines levels were sequentially measured, thirteen endothelial markers were determined at admission and at the zenith of the cytokines. Computed tomography scans on admission were quantified for lung damage and hepatic steatosis (n = 23). Abnormal BMI (> 25) observed in 72.6% of patients, was associated with a higher rate of intensive care unit hospitalization (p = 0.044). SARS-CoV-2 RNAaemia, peripheral immune cell subsets and cytokines/chemokines were similar among BMI groups. A significant association between inflammatory cytokines and liver, renal, and endothelial dysfunctions was observed only in patients with obesity (BMI > 30). In contrast, early signs of lung damage (ground-glass opacity) correlated with Th1/M1/inflammatory cytokines only in normal weight patients. Later lesions of pulmonary consolidation correlated with BMI but were independent of cytokine levels. Our study reveals distinct physiopathological mechanisms associated with SARS-CoV-2 infection in patients with obesity that may have important clinical implications.


Subject(s)
COVID-19/pathology , Cytokines/metabolism , Liver/physiopathology , Lung/physiopathology , Obesity/pathology , Aged , Biomarkers/metabolism , Body Mass Index , COVID-19/complications , COVID-19/virology , Chemokines/blood , Chemokines/metabolism , Cytokines/blood , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Female , Hospitalization/statistics & numerical data , Humans , Intensive Care Units , Liver/diagnostic imaging , Lung/diagnostic imaging , Male , Middle Aged , Obesity/complications , Prospective Studies , RNA, Viral/blood , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Severity of Illness Index
17.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1243489

ABSTRACT

We analyzed plasma levels of interferons (IFNs) and cytokines, and expression of IFN-stimulated genes in peripheral blood mononuclear cells in patients with coronavirus disease 2019 of varying disease severity. Patients hospitalized with mild disease exhibited transient type I IFN responses, while intensive care unit patients had prolonged type I IFN responses. Type II IFN responses were compromised in intensive care unit patients. Type III IFN responses were induced in the early phase of infection, even in convalescent patients. These results highlight the importance of early type I and III IFN responses in controlling coronavirus disease 2019 progression.


Subject(s)
COVID-19/immunology , Interferon Type I/immunology , Interferon-gamma/immunology , Interferons/immunology , COVID-19/blood , Chemokines/blood , Cytokines/blood , Humans , Interferon Type I/blood , Interferon Type I/genetics , Interferon-gamma/blood , Interferon-gamma/genetics , Interferons/blood , Leukocytes, Mononuclear/immunology , SARS-CoV-2/isolation & purification
18.
J Infect Dis ; 223(9): 1512-1521, 2021 05 20.
Article in English | MEDLINE | ID: covidwho-1238201

ABSTRACT

Lower respiratory tract (LRT) disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can deteriorate to acute respiratory distress syndrome (ARDS). Because the release of neutrophil extracellular traps (NETs) is implicated in ARDS pathogenesis, we investigated the presence of NETs and correlates of pathogenesis in blood and LRT samples of critically ill patients with COVID-19. Plasma NET levels peaked early after intensive care unit admission and were correlated with the SARS-CoV-2 RNA load in sputum and levels of neutrophil-recruiting chemokines and inflammatory markers in plasma samples. The baseline plasma NET quantity was correlated with disease severity but was not associated with soluble markers of thrombosis or with development of thrombosis. High NET levels were present in LRT samples and persisted during the course of COVID-19, consistent with the detection of NETs in bronchi and alveolar spaces in lung tissue from deceased patient with COVID-19. Thus, NETs are produced and retained in the LRT of critically ill patients with COVID-19 and could contribute to SARS-CoV-2-induced ARDS disease.


Subject(s)
Bronchoalveolar Lavage Fluid/virology , COVID-19/complications , COVID-19/pathology , Extracellular Traps/virology , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/pathology , SARS-CoV-2 , Adult , Aged , Biomarkers , Chemokines/blood , Cohort Studies , Computed Tomography Angiography , Critical Illness , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunohistochemistry , Male , Middle Aged , Netherlands/epidemiology , Prospective Studies , Severity of Illness Index , Thrombosis/virology , Viral Load
19.
J Med Virol ; 93(5): 2828-2837, 2021 05.
Article in English | MEDLINE | ID: covidwho-1196519

ABSTRACT

The disease course of children with coronavirus disease 2019 (COVID-19) seems milder as compared with adults, however, actual reason of the pathogenesis still remains unclear. There is a growing interest on possible relationship between pathogenicity or disease severity and biomarkers including cytokines or chemokines. We wondered whether these biomarkers could be used for the prediction of the prognosis of COVID-19 and improving our understanding on the variations between pediatric and adult cases with COVID-19. The acute phase serum levels of 25 cytokines and chemokines in the serum samples from 60 COVID-19 pediatric (n = 30) and adult cases (n = 30) including 20 severe or critically ill, 25 moderate and 15 mild patients and 30 healthy pediatric (n = 15) and adult (n = 15) volunteers were measured using commercially available fluorescent bead immunoassay and analyzed in combination with clinical data. Interferon gamma-induced protein 10 (IP-10) and macrophage inflammatory protein (MIP)-3ß levels were significantly higher in patient cohort including pediatric and adult cases with COVID-19 when compared with all healthy volunteers (p ≤ .001 in each) and whereas IP-10 levels were significantly higher in both pediatric and adult cases with severe disease course, MIP-3ß were significantly lower in healthy controls. Additionally, IP-10 is an independent predictor for disease severity, particularly in children and interleukin-6 seems a relatively good predictor for disease severity in adults. IP-10 and MIP-3ß seem good research candidates to understand severity of COVID-19 in both pediatric and adult population and to investigate possible pathophysiological mechanism of COVID-19.


Subject(s)
Biomarkers/blood , COVID-19/therapy , Chemokines/blood , Cytokines/blood , Severity of Illness Index , Adolescent , Aged , Chemokine CCL19/blood , Chemokine CXCL10/blood , Child , Child, Preschool , Disease Progression , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Prognosis , SARS-CoV-2
20.
EBioMedicine ; 66: 103317, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1163669

ABSTRACT

BACKGROUND: SARS-CoV-2 infection in children can present with varied clinical phenotypes and understanding the pathogenesis is essential, to inform about the clinical trajectory and management. METHODS: We performed a multiplex immune assay analysis and compared the plasma biomarkers of Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS), acute COVID-19 infection (COVID-19), SARS-CoV-2 seropositive and control children admitted to a tertiary care children's hospital in Chennai, India. Pro-inflammatory cytokines, chemokines and growth factors were correlated with SARS-CoV-2 clinical phenotypes. FINDINGS: PIMS-TS children had significantly elevated levels of cytokines, IFNγ, IL-2, TNFα, IL-1α, IFNα, IFNß, IL-6, IL-15, IL-17A, GM-CSF, IL-10, IL-33 and IL-Ra; elevated chemokines, CCL2, CCL19, CCL20 and CXCL10 and elevated VEGF, Granzyme B and PDL-1 in comparison to COVID-19, seropositive and controls. COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IFNα, IFNß, IL-6, IL-17A, IL-10, CCL2, CCL5, CCL11, CXCL10 and VEGF in comparison to seropositive and/or controls. Similarly, seropositive children had elevated levels of IFNγ, IL-2, IL-1α, IFNß, IL-17A, IL-10, CCL5 and CXCL10 in comparison to control children. Plasma biomarkers in PIMS-TS and COVID-19 children showed a positive correlation with CRP and a negative correlation with the lymphocyte count and sodium levels. INTERPRETATION: We describe a comprehensive plasma biomarker profile of children with different clinical spectrum of SARS-CoV-2 infection from a low- and middle-income country (LMIC) and observed that PIMS-TS is a distinct and unique immunopathogenic paediatric illness related to SARS-CoV-2 presenting with cytokine storm different from acute COVID-19 infection and other hyperinflammatory conditions.


Subject(s)
Biomarkers/blood , COVID-19/blood , Systemic Inflammatory Response Syndrome/blood , Adolescent , C-Reactive Protein/analysis , COVID-19/etiology , COVID-19/virology , COVID-19 Serological Testing , Case-Control Studies , Chemokines/blood , Child , Child, Preschool , Cytokines/blood , Female , Humans , India , Infant , Intercellular Signaling Peptides and Proteins/blood , Lymphocyte Count , Male , Systemic Inflammatory Response Syndrome/etiology , Systemic Inflammatory Response Syndrome/virology
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