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1.
J Infect Dis ; 224(5): 777-782, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467988

RESUMO

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.


Assuntos
COVID-19/imunologia , Interferon Tipo I/imunologia , Interferon gama/imunologia , Interferons/imunologia , COVID-19/sangue , Quimiocinas/sangue , Citocinas/sangue , Humanos , Interferon Tipo I/sangue , Interferon Tipo I/genética , Interferon gama/sangue , Interferon gama/genética , Interferons/sangue , Leucócitos Mononucleares/imunologia , SARS-CoV-2/isolamento & purificação
2.
Front Immunol ; 12: 681516, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489933

RESUMO

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.


Assuntos
COVID-19/imunologia , Citocinas/genética , Citocinas/imunologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Transcriptoma/imunologia , Adulto , Idoso , Biomarcadores/sangue , Quimiocinas/sangue , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/sangue , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Influenza Humana/sangue , Influenza Humana/imunologia , Masculino , Pessoa de Meia-Idade
3.
Biomolecules ; 11(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34439815

RESUMO

BACKGROUND: Chemerin is an adipokine and a chemoattractant for leukocytes. Increased chemerin levels were observed in patients with coronary artery disease (CAD). We investigated associations between chemerin and biochemical measurements or body composition in CAD patients. METHODS: In the study, we included patients with stable CAD who had undergone percutaneous coronary intervention (PCI) in the past. All patients had routine blood tests, and their insulin and chemerin serum levels were routinely measured. Body composition was assessed with the DEXA method. RESULTS: The study group comprised 163 patients (mean age 59.8 ± years, 26% of females, n = 43). There was no significant difference in serum chemerin concentrations between patients with diabetes and the remaining ones: 306.8 ± 121 vs. 274.15 ± 109 pg/mL, p = 0.1. Chemerin correlated positively with the white blood cell (WBC) count, the neutrophil to lymphocyte ratio, hsCRP, all fractions of cholesterol, triglycerides, platelet count, fasting insulin, and c-peptide. Chemerin levels were also correlated with total fat mass but only in a subgroup with normal glucose metabolism. CONCLUSION: In patients with CAD, serum chemerin levels are correlated with inflammation markers, insulin resistance, and an unfavorable lipid profile. Correlation with fat mass is dependent on glucose metabolism status. Depending on the presence of diabetes/prediabetes, the mechanisms regulating chemerin secretion may be different.


Assuntos
Plaquetas/metabolismo , Quimiocinas/genética , Doença da Artéria Coronariana/sangue , Diabetes Mellitus Tipo 2/sangue , Linfócitos/metabolismo , Neutrófilos/metabolismo , Idoso , Glicemia/metabolismo , Plaquetas/patologia , Composição Corporal , Peptídeo C/sangue , Proteína C-Reativa/metabolismo , Quimiocinas/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/terapia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Feminino , Humanos , Inflamação , Insulina/sangue , Resistência à Insulina , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Intervenção Coronária Percutânea , Projetos Piloto , Triglicerídeos/sangue
4.
PLoS One ; 16(8): e0256784, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34460840

RESUMO

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).


Assuntos
COVID-19/patologia , Metabolômica , Sepse/diagnóstico , Adulto , Área Sob a Curva , COVID-19/complicações , COVID-19/virologia , Quimiocinas/sangue , Citocinas/sangue , Feminino , Humanos , Cinurenina/sangue , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Curva ROC , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Sepse/etiologia , Índice de Gravidade de Doença , Triptofano/sangue
5.
Am J Mens Health ; 15(4): 15579883211034984, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34330167

RESUMO

Chemerin (CHEM) is a new proinflammatory adipokine involved in the immune, metabolic and reproductive processes. Low-grade state inflammation (LGSI) is a key element in the pathogenesis of metabolic syndrome (MS). Low SHBG is a good marker of male hypogonadism in MS. This study evaluated the prognostic value of selected adipokine, LGSI, and androgenic parameters in predicting the risk of MS among men. One hundred thirty-two random men aged 40 to 70 years old were enrolled. Measurements of anthropometric indices, blood pressure, and laboratory tests were carried out. A total of 62 men (47%) were diagnosed with MS. Chemerin concentrations were higher in men diagnosed with MS compared to healthy: 89.48 (78.12-112.10) vs. 77.9 (65.12-98.64) ng/mL; p = .002. Men diagnosed with MS presented with lower levels of total testosterone: 5.75 (4.00-6.57) vs. 6.40 (5.50-8.40) ng/mL; p = .0014 and SHBG: 46.58 (35.13-66.28) vs. 71.97 (56.1-92.7) nM/L; p < 0.000001. Elevated LGSI indices were demonstrated in men with MS as opposed to healthy [IL-18: 530.64 (409.12-640.56) vs. 418.85 (348.14-496.44) pg/mL; p = .000033 and hs-CRP: 2.15 (0.97-4.26) vs. 1.01 (0.41-2.68) ng/mL; p = .0057)]. In multivariate regression analysis, the highest negative predictive value in assessing the risk of MS was SHBG serum concentration, while the highest positive predictive values were: IL-18, hypertriglyceridemia, and waist circumference. Decreased SHBG levels, combined with elevated IL-18 concentrations in men showing hypertriglyceridemic waist phenotype, significantly increase the risk of MS.


Assuntos
Androgênios/sangue , Quimiocinas/sangue , Interleucina-18/sangue , Síndrome Metabólica/diagnóstico , Testosterona/sangue , Adulto , Idoso , Estudos de Casos e Controles , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Circunferência da Cintura
6.
PLoS One ; 16(7): e0254367, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34242356

RESUMO

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.


Assuntos
Anticorpos Antivirais , COVID-19 , Quimiocinas , Proteínas do Nucleocapsídeo de Coronavírus , Imunoglobulina G , Imunoglobulina M , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Adulto , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/imunologia , Quimiocinas/sangue , Quimiocinas/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/sangue , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/sangue , Fosfoproteínas/imunologia , Coelhos , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/sangue , Glicoproteína da Espícula de Coronavírus/imunologia
7.
Life Sci Alliance ; 4(9)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34321327

RESUMO

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.


Assuntos
COVID-19/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Administração Intravenosa , Adulto , Idoso , Biomarcadores/sangue , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Quimiocinas/sangue , Citocinas/sangue , Feminino , Humanos , Imunidade/imunologia , Imunoglobulinas/imunologia , Imunoglobulinas/uso terapêutico , Imunoglobulinas Intravenosas/imunologia , Inflamação/sangue , Inflamação/terapia , Inflamação/virologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação
8.
Front Immunol ; 12: 668725, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276659

RESUMO

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.


Assuntos
Anafilatoxinas/análise , COVID-19/sangue , COVID-19/mortalidade , Quimiocinas/sangue , Mortalidade Hospitalar , SARS-CoV-2/genética , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/virologia , Estudos de Casos e Controles , Síndrome da Liberação de Citocina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
9.
Clin Immunol ; 229: 108790, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34197952

RESUMO

Because of their rarity, limited awareness among non-specialists, and significant overlaps in their clinical presentation, childhood autoimmune/inflammatory conditions represent a diagnostic and therapeutic challenge. Juvenile idiopathic arthritis (JIA), with its 7 sub-forms, is the most common paediatric "rheumatic" disease. Juvenile-onset systemic lupus erythematosus (jSLE) is a severe autoimmune/inflammatory disease that can affect any organ system and shares clinical features with JIA. To overcome issues around diagnostic approaches in the context of clinical overlap, we aimed at the definition of disease sub-form specific cytokine and chemokine profiles. Serum samples from patients with JIA (n = 77) and jSLE (n = 48), as well as healthy controls (n = 30), were collected. Samples were analysed using the Meso Scale Discovery (MSD) U-PLEX Biomarker Group 1 (hu) panel. Distinct serum protein signatures associate with JIA vs jSLE disease groups. Proteins with high discriminatory ability include IL-23, MIP-1ß, MCP-1, M-CSF and MDC. Furthermore, serum IL-18, MIF, MIP-5 and YKL-40 discriminate between systemic JIA and other JIA subtypes. Thus, simultaneous quantification of serum proteins in a panel format may provide an avenue for the diagnosis and monitoring of childhood autoimmune/inflammatory conditions.


Assuntos
Artrite Juvenil/sangue , Artrite Juvenil/diagnóstico , Proteínas Sanguíneas/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Adolescente , Artrite Juvenil/classificação , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocinas/sangue , Criança , Citocinas/sangue , Diagnóstico Diferencial , Feminino , Humanos , Masculino
10.
Trop Med Int Health ; 26(9): 1098-1109, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107115

RESUMO

OBJECTIVES: We measured the production of cytokines, chemokines and antibodies involved in allergic responses and sCD23 levels during Schistosoma mansoni infection. METHODS: Individuals (n = 164) were selected using the ISAAC questionnaire and parasitological exams. The subjects were divided as follows: those infected individuals with allergy-related symptoms (A-I), those with allergy-related symptoms only (A-NI); those only infected (NA-I); and those non-infected individuals without allergy-related symptoms (NA-NI). We used supernatants from cell culture (mitogenic stimulation) to measure cytokine and chemokine levels using cytometric bead arrays. Serum levels of anti-Ascaris lumbricoides (Asc) and anti-Blomia tropicalis IgE were measured using ImmunoCAP, and sCD23 was measured using ELISA. RESULTS: Schistosoma mansoni infection was associated with a lower risk of allergy-related symptoms. In A-I, there were higher levels of TNF-α, IL-10, IL-6, IFN-γ and CXCL8 than in NA-NI group, with TNF-α and IL-6 also at higher levels compared to A-NI group. Levels of IL-6, CXCL8, total and anti-Asc IgE, as well as the numbers of eosinophils, were higher in NA-I than in NA-NI, and the antibodies were also lower in A-NI than in NA-I group. In AI and NA-I, there was less production of CCL2 than in NA-NI. There were no differences in the levels of IL-2, IL-4, IL-17, CCL5, sCD23 and anti-Blomia IgE. CONCLUSIONS: Patients with allergy-related symptoms and infected (simultaneously) had higher levels of IL-10; due to the infection, there was increased production of IL-6 and CXCL8 and less CCL2. These data may characterize deviation to Th1 or attenuation of the Th2 response in allergy sufferers in areas endemic for schistosomiasis.


Assuntos
Anticorpos/imunologia , Quimiocinas/imunologia , Citocinas/imunologia , Hipersensibilidade Respiratória/parasitologia , Esquistossomose mansoni/imunologia , Adolescente , Adulto , Animais , Anticorpos/sangue , Anticorpos Anti-Helmínticos/sangue , Anticorpos Anti-Helmínticos/imunologia , Brasil/epidemiologia , Quimiocina CCL2/imunologia , Quimiocinas/sangue , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Humanos , Imunoglobulina E , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
J Med Virol ; 93(10): 5805-5815, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34061395

RESUMO

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.


Assuntos
COVID-19/diagnóstico , Citocinas/sangue , Adulto , Bangladesh/epidemiologia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Quimiocinas/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Carga Viral
12.
PLoS One ; 16(6): e0253487, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34161386

RESUMO

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.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , COVID-19/terapia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/genética , Animais , Anticorpos Neutralizantes/metabolismo , COVID-19/imunologia , COVID-19/virologia , Quimiocinas/sangue , Quimiocinas/genética , Chlorocebus aethiops , Convalescença , Cricetinae , Citocinas/sangue , Citocinas/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/isolamento & purificação , Macaca mulatta , Masculino , Camundongos Transgênicos , Glicoproteína da Espícula de Coronavírus/metabolismo , Células Vero , Carga Viral
13.
PLoS One ; 16(5): e0252026, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34038475

RESUMO

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.


Assuntos
COVID-19/patologia , Citocinas/metabolismo , Fígado/fisiopatologia , Pulmão/fisiopatologia , Obesidade/patologia , Idoso , Biomarcadores/metabolismo , Índice de Massa Corporal , COVID-19/complicações , COVID-19/virologia , Quimiocinas/sangue , Quimiocinas/metabolismo , Citocinas/sangue , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva , Fígado/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Estudos Prospectivos , RNA Viral/sangue , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
14.
Cells ; 10(4)2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805274

RESUMO

Normothermic machine perfusion is clinically used to assess the quality of marginal donor lungs. Although subnormothermic temperatures have proven beneficial for other solid organ transplants, subnormothermia-related benefits of ex vivo lung perfusion (EVLP) still need to be investigated. Material and Methods: In a rat model, we evaluated the effects of 28 °C temperature on 4-h EVLPs with subsequent left lung transplantation. The recipients were observed for 2 h postoperatively. Lung physiology data were recorded and metabolic parameters were assessed. Results: During the 4-h subnormothermic EVLP, the lung oxygenation was significantly higher (p < 0.001), pulmonary vascular resistance (PVR) lower and dynamic compliance (Cdyn) higher when compared to the 37 °C EVLP. During an end-of-EVLP stress test, we recorded significantly higher flow (p < 0.05), lower PVR (p < 0.05) and higher Cdyn (p < 0.01) in the 28 °C group when compared to the 37 °C group. After the left lung transplantation, Cdyn and oxygenation improved in the 28 °C group, which were comparable to the 37 °C group. Chemokines RANTES, MIP-3α, MIP-1α MCP-1 GRO/KC and pro-inflammatory mediators GM-CSF, G-CSF and TNFα were significantly lower after the 28 °C EVLP and remained low in the plasma of the recipient rats after transplantation. The lungs of the 28 °C group showed significantly lowered myeloperoxidase activity and lowered levels of TNFα and IL-1ß. Conclusions: Compared to the normothermic perfusion, the 28 °C EVLP improved Cdyn and PVR and reduced both the release of pro-inflammatory cytokines and myeloperoxidase activity in lung tissue. These observations were also observed after the left lung transplantation in the subnormothermic group. The 28 °C EVLP significantly improved biochemical, physiological and inflammatory parameters in lung donors.


Assuntos
Transplante de Pulmão , Pulmão/fisiologia , Perfusão , Temperatura , Trifosfato de Adenosina/metabolismo , Animais , Quimiocinas/sangue , Pulmão/citologia , Masculino , Oxigênio/metabolismo , Peroxidase/metabolismo , Carbonilação Proteica , Ratos Sprague-Dawley , Resistência Vascular
15.
Arq Neuropsiquiatr ; 79(3): 189-194, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33886791

RESUMO

BACKGROUND: Elevated levels of chemerin can predict future ischemic cerebrovascular disease. Although chemerin is thought to play a role in atherosclerotic inflammation, whether circulating chemerin levels are associated with the severity of atherosclerosis remains to be determined. OBJECTIVES: Through the use of carotid Doppler ultrasonography, our aim in this study was to investigate the relationships of serum chemerin levels with carotid intima-media thickness (CIMT) as an indicator of generalized atherosclerosis. METHODS: This study compared 40 patients with ischemic stroke and 40 healthy subjects. Measurements were made at end-diastole using color Doppler ultrasonography (CDUS) after a 5-min rest interval in a quiet and dark room. CIMT was defined as the distance between the innermost edge of the luminal echo to the innermost edge of the media/adventitia echo. CIMT was measured in the posterior wall of both common carotid arteries within 1 cm proximally to the bulbus. Three measurements were made on both sides and the average measurement was taken as the CIMT. Serum chemerin levels were determined in all patients and healthy subjects. RESULTS: Serum chemerin levels were significantly higher in the patient group than in the control group (p=0.004). Serum chemerin levels were positively correlated with CIMT (p<0.05). There was a significant difference between the groups with regard to CIMT (p<0.001). CONCLUSION: Elevated serum chemerin levels appear to be associated with CIMT, thus suggesting that a link exists between chemerin and atherosclerotic ischemic cerebrovascular disease.


Assuntos
Aterosclerose , Doenças das Artérias Carótidas , Espessura Intima-Media Carotídea , Quimiocinas/sangue , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Artéria Carótida Primitiva/diagnóstico por imagem , Humanos , Fatores de Risco , Ultrassonografia
16.
EBioMedicine ; 66: 103317, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813138

RESUMO

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.


Assuntos
Biomarcadores/sangue , COVID-19/sangue , Síndrome de Resposta Inflamatória Sistêmica/sangue , Adolescente , Proteína C-Reativa/análise , COVID-19/etiologia , COVID-19/virologia , Teste Sorológico para COVID-19 , Estudos de Casos e Controles , Quimiocinas/sangue , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Humanos , Índia , Lactente , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Contagem de Linfócitos , Masculino , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/virologia
17.
J Med Virol ; 93(7): 4559-4563, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33811680

RESUMO

Coronavirus disease 2019 (COVID-19) is globally rampant, and to curb the growing burden of this disease, in-depth knowledge about its pathophysiology is needed. This was an observational study conducted at a single center to investigate serum cytokine and chemokine levels of COVID-19 patients, based on disease severity. We included 72 consecutive COVID-19 patients admitted to our hospital from March 21 to August 31, 2020. Patients were divided into Mild-Moderate I (mild) and Moderate II-Severe (severe) groups based on the COVID-19 severity classification developed by the Ministry of Health, Labor and Welfare (MHLW) of Japan. We compared the patient characteristics as well as the serum cytokine and chemokine levels on the day of admission between the two groups. Our findings indicated that the severe group had significantly higher levels of serum fibrinogen, d-dimer, lactate dehydrogenase, C-reactive protein, ferritin, Krebs von den Lungen-6, surfactant protein (SP)-D, and SP-A than the mild group. Strikingly, the levels of interleukin (IL)-28A/interferon (IFN)-λ2 were significantly lower in the severe group than in the mild group. We believe that reduced levels of type III interferons (IFN-λs) and alterations in the levels of other cytokines and chemokines may impact the severity of the disease.


Assuntos
COVID-19/sangue , Quimiocinas/sangue , Interferons/sangue , SARS-CoV-2/imunologia , Adulto , Idoso , Proteína C-Reativa/análise , COVID-19/patologia , Regulação para Baixo , Feminino , Ferritinas/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Humanos , Interferons/biossíntese , Interleucinas/sangue , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Mucina-1/sangue , Proteína A Associada a Surfactante Pulmonar/sangue , Proteína D Associada a Surfactante Pulmonar/sangue , Índice de Gravidade de Doença
18.
Front Immunol ; 12: 630934, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777015

RESUMO

Schistosomiasis and Leishmaniasis are chronic parasitic diseases with high prevalence in some tropical regions and, due to their wide distribution, a risk of co-infections is present in some areas. Nevertheless, the impact of this interaction on human populations is still poorly understood. Thus, the current study evaluated the effect of previous American Tegumentary Leishmaniasis (ATL) on the susceptibility and immune response to Schistosoma mansoni infection in residents from a rural community in Northern of Minas Gerais state, Brazil, an area endemic for both parasitic infections. The participants answered a socioeconomic questionnaire and provided stool and blood samples for parasitological and immunological evaluations. Stool samples were examined by a combination of parasitological techniques to identify helminth infections, especially S. mansoni eggs. Blood samples were used for hemograms and to measure the serum levels of cytokines and chemokines. Reports on previous ATL were obtained through interviews, clinical evaluation forms, and medical records. S. mansoni infection was the most prevalent parasitic infection in the study population (46%), and the majority of the infected individuals had a very low parasite burden. In the same population, 93 individuals (36.2%) reported previous ATL, and the prevalence of S. mansoni infection among these individuals was significantly higher than among individuals with no ATL history. A multiple logistic regression model revealed that S. mansoni infection was positively associated with higher levels of CCL3 and CCL17, and a higher frequency of IL-17 responders. Moreover, this model demonstrated that individuals with an ATL history had a 2-fold higher probability to be infected with S. mansoni (OR = 2.0; 95% CI 1.04-3.68). Among S. mansoni-infected individuals, the logistic regression demonstrated that a previous ATL history was negatively associated with the frequency of IL-17 responders and CXCL10 higher responders, but positively associated with higher IL-27 responders. Altogether, our data suggest that previous ATL may alter the susceptibility and the immune response in S. mansoni-infected individuals, which may likely affect the outcome of schistosomiasis and the severity of the disease in humans.


Assuntos
Leishmaniose Cutânea/imunologia , Esquistossomose mansoni/imunologia , Adolescente , Adulto , Quimiocinas/sangue , Criança , Citocinas/sangue , Suscetibilidade a Doenças , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Esquistossomose mansoni/sangue , Adulto Jovem
19.
Front Immunol ; 12: 616305, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717107

RESUMO

Dyslipidemia promotes development of the atherosclerotic plaques that characterise cardiovascular disease. Plaque progression requires the influx of monocytes into the vessel wall, but whether dyslipidemia is associated with an increased potential of monocytes to extravasate is largely unknown. Here (using flow cytometry) we examined recruitment marker expression on monocytes from generally healthy individuals who differed in lipid profile. Comparisons were made between monocyte subsets, participants and relative to participants' lipid levels. Monocyte subsets differed significantly in their expression of recruitment markers, with highest expression being on either the classical or non-classical subsets. However, these inter-subset differences were largely overshadowed by considerable inter-participant differences with some participants having higher levels of recruitment markers on all three monocyte subsets. Furthermore, when the expression of one recruitment marker was high, so too was that of most of the other markers, with substantial correlations evident between the markers. The inter-participant differences were explained by lipid levels. Most notably, there was a significant inverse correlation for most markers with ApoA1 levels. Our results indicate that dyslipidemia, in particular low levels of ApoA1, is associated with an increased potential of all monocyte subsets to extravasate, and to do so using a wider repertoire of recruitment markers than currently appreciated.


Assuntos
Apolipoproteína A-I/sangue , Biomarcadores , Quimiotaxia de Leucócito/imunologia , Monócitos/imunologia , Monócitos/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Moléculas de Adesão Celular/sangue , Quimiocinas/sangue , Humanos , Imunofenotipagem , Pessoa de Meia-Idade
20.
Biomolecules ; 11(2)2021 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-33669910

RESUMO

Adiponectin, leptin, and resistin are adipocytokines whose levels are elevated in blood and synovial fluid from patients with rheumatoid arthritis (RA). However, their role in RA pathogenesis is unclear. Here, we examined whether adipocytokines are associated with circulating chemokines, markers of inflammation and RA disease activity in patients with untreated newly diagnosed RA. Plasma levels of 15 chemokines, adiponectin, leptin, and resistin were measured using flow cytometry bead-based immunoassay or enzyme-linked immunosorbent assay (ELISA) in a cohort of 70 patients with untreated newly diagnosed RA. Markers of inflammation and disease activity were also assessed in all patients. Positive association was found between total adiponectin and CXCL10 (ß = 0.344, p = 0.021), CCL2 (ß = 0.342, p = 0.012), and CXCL9 (ß = 0.308, p = 0.044), whereas high-molecular weight (HMW) adiponectin associated only with CXCL9 (ß = 0.308, p = 0.033). Furthermore, both total and HMW adiponectin were associated with C-reactive protein (ß = 0.485, p = 0.001; ß = 0.463, p = 0.001) and erythrocyte sedimentation rate (ß = 0.442, p = 0.001; ß = 0.507, p < 0.001). Leptin and resistin were not associated with plasma chemokines, markers of inflammation, or disease activity scores. Our study shows an association between circulating adiponectin and pro-inflammatory chemokines involved in RA pathogenesis as well as markers of inflammation in a well-characterized cohort of patients with untreated newly diagnosed RA.


Assuntos
Adipocinas/metabolismo , Adiponectina/sangue , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Leptina/sangue , Resistina/sangue , Adipocinas/sangue , Adulto , Quimiocinas/sangue , Estudos de Coortes , Feminino , Humanos , Inflamação , Leptina/metabolismo , Masculino , Pessoa de Meia-Idade , Tretinoína/metabolismo
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