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1.
Signal Transduct Target Ther ; 5(1): 186, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883951

RESUMO

Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.


Assuntos
Betacoronavirus/patogenicidade , Colesterol/biossíntese , Infecções por Coronavirus/genética , Síndrome da Liberação de Citocina/genética , Interações Hospedeiro-Patógeno/genética , Leucócitos Mononucleares/imunologia , Pneumonia Viral/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Betacoronavirus/imunologia , Estudos de Casos e Controles , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Unidades de Terapia Intensiva , Interleucina-1beta/genética , Interleucina-1beta/imunologia , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , NF-kappa B/genética , NF-kappa B/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Cultura Primária de Células , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/imunologia , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/imunologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
2.
Cell Mol Immunol ; 17(10): 1092-1094, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32917983
3.
Crit Rev Immunol ; 40(2): 167-171, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749094

RESUMO

Coronavirus disease 2019 (COVID-19) poses a great public health challenge worldwide. While studies on the effects of SARS-CoV-2 on immune cell function continue to progress, we know very little about the significance of depletion of key immune effectors by the virus in the mortality and morbidity of the disease. This commentary reviews what is known thus far about the effects of the virus on natural killer (NK) cells, the major cell type responsible for the destruction and removal of virally infected cells. It also highlights the necessity of comprehensive studies of NK cells in COVID-19 patients and animal models to better understand the role and significance of reported NK depletion and functional inactivation in disease morbidity and mortality, in the hopes of designing effective therapeutic interventions for the disease.


Assuntos
Infecções por Coronavirus/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/virologia , Pneumonia Viral/patologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Betacoronavirus/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Humanos , Interferon gama/imunologia , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Fator de Necrose Tumoral alfa/imunologia
4.
Adv Biol Regul ; 77: 100737, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773100

RESUMO

Natural killer (NK) cells are pivotal effectors of the innate immunity protecting an individual from microbes. They are the first line of defense against invading viruses, given their substantial ability to directly target infected cells without the need for specific antigen presentation. By establishing cellular networks with a variety of cell types such as dendritic cells, NK cells can also amplify and modulate antiviral adaptive immune responses. In this review, we will examine the role of NK cells in SARS-COV2 infections causing the ongoing COVID19 pandemic, keeping in mind the controversial role of NK cells specifically in viral respiratory infections and in inflammatory-driven lung damage. We discuss lessons learnt from previous coronavirus outbreaks in humans (caused by SARS-CoV-1 and MERS-COV).


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Interações Hospedeiro-Patógeno/imunologia , Células Matadoras Naturais/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Insuficiência Respiratória/epidemiologia , Doença Aguda , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Regulação da Expressão Gênica , Imunidade Inata , Interferon gama/genética , Interferon gama/imunologia , Interleucinas/genética , Interleucinas/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Ativação Linfocitária , Proteína 1 de Membrana Associada ao Lisossomo/genética , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
5.
Nat Rev Immunol ; 20(10): 585-586, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32788708
7.
Am J Gastroenterol ; 115(10): 1722-1724, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32826572

RESUMO

INTRODUCTION: It has been hypothesized that people suffering from inflammatory bowel disease (IBD) have an increased risk of coronavirus disease (COVID-19). However, it is not known whether immunosuppressive therapies exacerbate the COVID-19 outcome. METHODS: We reviewed data on the prevalence and clinical outcomes of COVID-19 in patients with IBD. RESULTS: COVID-19 prevalence in patients with IBD was comparable with that in the general population. Therapies using antitumor necrosis factor-α agents have been associated with better clinical outcomes. DISCUSSION: Management and treatments provided by gastroenterologists were effective in reducing COVID-19 risk. Antitumor necrosis factor-α agents seem to mitigate the course of COVID-19.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Pneumonia Viral/epidemiologia , Fator de Necrose Tumoral alfa/uso terapêutico , Betacoronavirus/isolamento & purificação , Técnicas de Laboratório Clínico/estatística & dados numéricos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Prevalência , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/farmacologia
8.
JCI Insight ; 5(17)2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32687484

RESUMO

COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-É£ and monocyte TFN-α production. Circulating T cell subsets were profoundly reduced in COVID-19 patients. Additionally, stimulated blood mononuclear cells produced less than 40%-50% of the IFN-É£ and TNF-α observed in septic and CINS patients, consistent with markedly impaired immune effector cell function. Approximately 25% of COVID-19 patients had increased IL-6 levels that were not associated with elevations in other canonical proinflammatory cytokines. Collectively, these findings support the hypothesis that COVID-19 suppresses host functional adaptive and innate immunity. Importantly, IL-7 administered ex vivo restored T cell IFN-É£ production in COVID-19 patients. Thus, ELISpot may functionally characterize host immunity in COVID-19 and inform prospective therapies.


Assuntos
Imunidade Adaptativa/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Pneumonia Viral/imunologia , Sepse/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Estudos de Casos e Controles , Estado Terminal , ELISPOT , Feminino , Voluntários Saudáveis , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Pandemias , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
9.
JCI Insight ; 5(17)2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32706339

RESUMO

BACKGROUNDElevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare with those observed in critically ill patients with acute respiratory distress syndrome (ARDS) or sepsis due to other causes.METHODSWe used a Luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTSFifteen hospitalized COVID-19 patients, 9 of whom were critically ill, were compared with critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1ß, IL-1RA, IL-6, IL-8, IL-18, and TNF-α between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONLevels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDINGFunding was received from NHLBI K23 HL125663 (AJR); The Bill and Melinda Gates Foundation OPP1113682 (AJR and CAB); Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687 NIH/NIAID U19AI057229-16; Stanford Maternal Child Health Research Institute; and Chan Zuckerberg Biohub (CAB).


Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Pneumonia Viral/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Sepse/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Síndrome da Liberação de Citocina/sangue , Citocinas/sangue , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-18/sangue , Interleucina-18/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Síndrome do Desconforto Respiratório do Adulto/sangue , Sepse/sangue , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
10.
JAMA Netw Open ; 3(6): e2010895, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: covidwho-505563

RESUMO

Importance: The epidemiologic and clinical characteristics of pediatric patients with coronavirus disease 2019 (COVID-19) have been reported, but information on immune features associated with disease severity is scarce. Objective: To delineate and compare the immunologic features of mild and moderate COVID-19 in pediatric patients. Design, Setting, and Participants: This single-center case series included 157 pediatric patients admitted to Wuhan Children's Hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data were collected from January 25 to April 18, 2020. Exposures: Documented SARS-CoV-2 infection. Main Outcomes and Measures: Clinical and immunologic characteristics were collected and analyzed. Outcomes were observed until April 18, 2020. Results: Of the 157 pediatric patients with COVID-19, 60 (38.2%) had mild clinical type with pneumonia, 88 (56.1%) had moderate cases, 6 (3.8%) had severe cases, and 3 (1.9%) were critically ill. The 148 children with mild or moderate disease had a median (interquartile range [IQR]) age of 84 (18-123) months, and 88 (59.5%) were girls. The most common laboratory abnormalities were increased levels of alanine aminotransferase (ALT) (median [IQR], 16.0 [12.0-26.0] U/L), aspartate aminotransferase (AST) (median [IQR], 30.0 [23.0-41.8] U/L), creatine kinase MB (CK-MB) activity (median [IQR], 24.0 [18.0-34.0] U/L), and lactate dehydrogenase (LDH) (median [IQR], 243.0 [203.0-297.0] U/L), which are associated with liver and myocardial injury. Compared with mild cases, levels of inflammatory cytokines including interleukin 6, tumor necrosis factor α, and interferon γ were unchanged, whereas the level of immune suppressive interleukin 10 was markedly increased in moderate cases compared with mild cases (median [IQR], 3.96 [3.34-5.29] pg/mL vs 3.58 [3.10-4.36] pg/mL; P = .048). There was no statistically significant difference in absolute number of lymphocytes (including T cells and B cells) between mild and moderate cases, but moderate cases were associated with a decrease in neutrophil levels compared with mild cases (median [IQR], 2310/µL [1680/µL-3510/µL] vs 3120/µL [2040/µL-4170/µL]; P = .01). Immunoglobin G and the neutrophil to lymphocyte ratio were negatively associated with biochemical indices related to liver and myocardial injury (immunoglobulin G, ALT: r, -0.3579; AST: r, -0.5280; CK-MB activity: r, -0.4786; LDH: r, -0.4984; and neutrophil to lymphocyte ratio, ALT: r, -0.1893; AST: r, -0.3912; CK-MB activity: r, -0.3428; LDH: r, -0.3234), while counts of lymphocytes, CD4+ T cells, and interleukin 10 showed positive associations (lymphocytes, ALT: r, 0.2055; AST: r, 0.3615; CK-MB activity: r, 0.338; LDH: r, 0.3309; CD4+ T cells, AST: r, 0.4701; CK-MB activity: r, 0.4151; LDH: r, 0.4418; interleukin 10, ALT: r, 0.2595; AST: r, 0.3386; CK-MB activity: r, 0.3948; LDH: r, 0.3794). Conclusions and Relevance: In this case series, systemic inflammation rarely occurred in pediatric patients with COVID-19, in contrast with the lymphopenia and aggravated inflammatory responses frequently observed in adults with COVID-19. Gaining a deeper understanding of the role of neutrophils, CD4+ T cells, and B cells in the pathogenesis of SARS-CoV-2 infection could be important for the clinical management of COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Citocinas/imunologia , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Distribuição por Idade , Alanina Transaminase/metabolismo , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Aspartato Aminotransferases/metabolismo , Linfócitos B/imunologia , Proteína C-Reativa/imunologia , Linfócitos T CD4-Positivos/imunologia , Criança , Pré-Escolar , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/terapia , Creatina Quinase Forma MB/metabolismo , Estado Terminal , Feminino , Hospitais Pediátricos , Humanos , Lactente , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-2/imunologia , Interleucina-4/imunologia , Interleucina-6/imunologia , Células Matadoras Naturais/imunologia , L-Lactato Desidrogenase/metabolismo , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/terapia , Índice de Gravidade de Doença , Distribuição por Sexo , Fator de Necrose Tumoral alfa/imunologia
11.
JAMA Netw Open ; 3(6): e2010895, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32492165

RESUMO

Importance: The epidemiologic and clinical characteristics of pediatric patients with coronavirus disease 2019 (COVID-19) have been reported, but information on immune features associated with disease severity is scarce. Objective: To delineate and compare the immunologic features of mild and moderate COVID-19 in pediatric patients. Design, Setting, and Participants: This single-center case series included 157 pediatric patients admitted to Wuhan Children's Hospital with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data were collected from January 25 to April 18, 2020. Exposures: Documented SARS-CoV-2 infection. Main Outcomes and Measures: Clinical and immunologic characteristics were collected and analyzed. Outcomes were observed until April 18, 2020. Results: Of the 157 pediatric patients with COVID-19, 60 (38.2%) had mild clinical type with pneumonia, 88 (56.1%) had moderate cases, 6 (3.8%) had severe cases, and 3 (1.9%) were critically ill. The 148 children with mild or moderate disease had a median (interquartile range [IQR]) age of 84 (18-123) months, and 88 (59.5%) were girls. The most common laboratory abnormalities were increased levels of alanine aminotransferase (ALT) (median [IQR], 16.0 [12.0-26.0] U/L), aspartate aminotransferase (AST) (median [IQR], 30.0 [23.0-41.8] U/L), creatine kinase MB (CK-MB) activity (median [IQR], 24.0 [18.0-34.0] U/L), and lactate dehydrogenase (LDH) (median [IQR], 243.0 [203.0-297.0] U/L), which are associated with liver and myocardial injury. Compared with mild cases, levels of inflammatory cytokines including interleukin 6, tumor necrosis factor α, and interferon γ were unchanged, whereas the level of immune suppressive interleukin 10 was markedly increased in moderate cases compared with mild cases (median [IQR], 3.96 [3.34-5.29] pg/mL vs 3.58 [3.10-4.36] pg/mL; P = .048). There was no statistically significant difference in absolute number of lymphocytes (including T cells and B cells) between mild and moderate cases, but moderate cases were associated with a decrease in neutrophil levels compared with mild cases (median [IQR], 2310/µL [1680/µL-3510/µL] vs 3120/µL [2040/µL-4170/µL]; P = .01). Immunoglobin G and the neutrophil to lymphocyte ratio were negatively associated with biochemical indices related to liver and myocardial injury (immunoglobulin G, ALT: r, -0.3579; AST: r, -0.5280; CK-MB activity: r, -0.4786; LDH: r, -0.4984; and neutrophil to lymphocyte ratio, ALT: r, -0.1893; AST: r, -0.3912; CK-MB activity: r, -0.3428; LDH: r, -0.3234), while counts of lymphocytes, CD4+ T cells, and interleukin 10 showed positive associations (lymphocytes, ALT: r, 0.2055; AST: r, 0.3615; CK-MB activity: r, 0.338; LDH: r, 0.3309; CD4+ T cells, AST: r, 0.4701; CK-MB activity: r, 0.4151; LDH: r, 0.4418; interleukin 10, ALT: r, 0.2595; AST: r, 0.3386; CK-MB activity: r, 0.3948; LDH: r, 0.3794). Conclusions and Relevance: In this case series, systemic inflammation rarely occurred in pediatric patients with COVID-19, in contrast with the lymphopenia and aggravated inflammatory responses frequently observed in adults with COVID-19. Gaining a deeper understanding of the role of neutrophils, CD4+ T cells, and B cells in the pathogenesis of SARS-CoV-2 infection could be important for the clinical management of COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Citocinas/imunologia , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Distribuição por Idade , Alanina Transaminase/metabolismo , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Aspartato Aminotransferases/metabolismo , Linfócitos B/imunologia , Proteína C-Reativa/imunologia , Linfócitos T CD4-Positivos/imunologia , Criança , Pré-Escolar , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/terapia , Creatina Quinase Forma MB/metabolismo , Estado Terminal , Feminino , Hospitais Pediátricos , Humanos , Lactente , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-2/imunologia , Interleucina-4/imunologia , Interleucina-6/imunologia , Células Matadoras Naturais/imunologia , L-Lactato Desidrogenase/metabolismo , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/terapia , Índice de Gravidade de Doença , Distribuição por Sexo , Fator de Necrose Tumoral alfa/imunologia
12.
JCI Insight ; 5(13)2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32544099

RESUMO

BACKGROUNDFatal cases of COVID-19 are increasing globally. We retrospectively investigated the potential of immunologic parameters as early predictors of COVID-19.METHODSA total of 1018 patients with confirmed COVID-19 were enrolled in our 2-center retrospective study. Clinical feature, laboratory test, immunological test, radiological findings, and outcomes data were collected. Univariate and multivariable logistic regression analyses were performed to evaluate factors associated with in-hospital mortality. Receiver operator characteristic (ROC) curves and survival curves were plotted to evaluate their clinical utility.RESULTSThe counts of all T lymphocyte subsets were markedly lower in nonsurvivors than in survivors, especially CD8+ T cells. Among all tested cytokines, IL-6 was elevated most significantly, with an upward trend of more than 10-fold. Using multivariate logistic regression analysis, IL-6 levels of more than 20 pg/mL and CD8+ T cell counts of less than 165 cells/µL were found to be associated with in-hospital mortality after adjusting for confounding factors. Groups with IL-6 levels of more than 20 pg/mL and CD8+ T cell counts of less than 165 cells/µL had a higher percentage of older and male patients as well as a higher proportion of patients with comorbidities, ventilation, intensive care unit admission, shock, and death. Furthermore, the receiver operating curve of the model combining IL-6 (>20 pg/mL) and CD8+ T cell counts (<165 cells/µL) displayed a more favorable discrimination than that of the CURB-65 score. The Hosmer-Lemeshow test showed a good fit of the model, with no statistical significance.CONCLUSIONIL-6 (>20 pg/mL) and CD8+ T cell counts (<165 cells/µL) are 2 reliable prognostic indicators that accurately stratify patients into risk categories and predict COVID-19 mortality.FundingThis work was supported by funding from the National Natural Science Foundation of China (no. 81772477 and 81201848).


Assuntos
Linfócitos T CD8-Positivos , Infecções por Coronavirus/imunologia , Mortalidade Hospitalar , Interleucina-6/imunologia , Pneumonia Viral/imunologia , Idoso , Área Sob a Curva , Betacoronavirus , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Feminino , Humanos , Interleucina-10/imunologia , Interleucina-8/imunologia , Modelos Logísticos , Contagem de Linfócitos , Linfopenia/sangue , Linfopenia/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Prognóstico , Curva ROC , Receptores de Interleucina-2/imunologia , Estudos Retrospectivos , Fator de Necrose Tumoral alfa/imunologia
13.
JCI Insight ; 5(13)2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32501293

RESUMO

BACKGROUND: Identifying immune correlates of COVID-19 disease severity is an urgent need for clinical management, vaccine evaluation, and drug development. Here, we present a temporal analysis of key immune mediators, cytokines, and chemokines in blood of hospitalized COVID-19 patients from serial sampling and follow-up over 4 weeks. METHODS: A total of 71 patients with laboratory-confirmed COVID-19 admitted to Beijing You'an Hospital in China with either mild (53 patients) or severe (18 patients) disease were enrolled with 18 healthy volunteers. We measured 34 immune mediators, cytokines, and chemokines in peripheral blood every 4-7 days over 1 month per patient using a bioplex multiplex immunoassay. RESULTS: We found that the chemokine RANTES (CCL5) was significantly elevated, from an early stage of the infection, in patients with mild but not severe disease. We also found that early production of inhibitory mediators including IL-10 and IL-1RA were significantly associated with disease severity, and a combination of CCL5, IL-1 receptor antagonist (IL-1RA), and IL-10 at week 1 may predict patient outcomes. The majority of cytokines that are known to be associated with the cytokine storm in virus infections such as IL-6 and IFN-γ were only significantly elevated in the late stage of severe COVID-19 illness. TNF-α and GM-CSF showed no significant differences between severe and mild cases. CONCLUSION: Together, our data suggest that early intervention to increase expression of CCL5 may prevent patients from developing severe illness. Our data also suggest that measurement of levels of CCL5, as well as IL-1RA and IL-10 in blood individually and in combination, might be useful prognostic biomarkers to guide treatment strategies.


Assuntos
Quimiocina CCL5/imunologia , Infecções por Coronavirus/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-10/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Betacoronavirus , Estudos de Casos e Controles , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Hospitalização , Humanos , Imunoensaio , Interferon gama/imunologia , Interleucina-6/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/imunologia
14.
Am J Med Sci ; 360(2): 112-119, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32534720

RESUMO

Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes mellitus, which is becoming increasingly prevalent throughout the world, with high mortality and morbidity. Because of the complex pathophysiological processes involved, DFU is difficult to treat effectively with traditional therapies. Ozone therapy, an emerging method, has been reported as potentially beneficial for closure of DFUs and may gradually move to the forefront of clinical practice. Possible mechanisms of action include antioxidant capacity, pathogen inactivation, vascular and endogenous growth factor modulation, and immune system activation. However, some researchers are skeptical about its safety, and clinical trials are lacking. This article reviews the current research and application of ozone therapy for DFUs.


Assuntos
Antibacterianos/uso terapêutico , Pé Diabético/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Oxidantes Fotoquímicos/uso terapêutico , Ozônio/uso terapêutico , Administração Retal , Administração Tópica , Transfusão de Sangue Autóloga , Pé Diabético/imunologia , Pé Diabético/metabolismo , Hemorreologia , Humanos , Peróxido de Hidrogênio/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferons/imunologia , Interleucina-2/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/imunologia
15.
Nat Rev Rheumatol ; 16(8): 465-470, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32561873

RESUMO

Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1ß or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19.


Assuntos
Artrite Reumatoide/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Alvéolos Pulmonares/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artralgia , Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Assistência à Saúde , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Inibidores de Janus Quinases/uso terapêutico , Mialgia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Reumatologia , Sulfonamidas/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/imunologia
17.
Proc Natl Acad Sci U S A ; 117(26): 15066-15074, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32554492

RESUMO

Cancer incidence increases exponentially with age when human telomeres are shorter. Similarly, telomerase reverse transcriptase (tert) mutant zebrafish have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a noncell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when wild-type (WT) tumors are generated in tert mutant zebrafish. Tissues adjacent to melanoma lesions (skin) and distant organs (intestine) in tert mutants exhibited higher levels of senescence and inflammation. In addition, we transferred second generation (G2) tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced increased tumor necrosis factor1-α (TNF1-α) expression and senescence in larval tissues in a noncell autonomous manner, creating an inflammatory environment. Considering that inflammation is protumorigenic, we transplanted melanoma-derived cells into G2 tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased tumor development. To test if inflammation was necessary for this effect, we treated melanoma transplants with nonsteroid anti-inflammatory drugs and show that higher melanoma dissemination can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence.


Assuntos
Melanoma/metabolismo , Telômero/metabolismo , Peixe-Zebra/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Melanoma/genética , Melanoma/imunologia , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Encurtamento do Telômero , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Peixe-Zebra/genética , Peixe-Zebra/imunologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
18.
Stem Cell Res Ther ; 11(1): 207, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: covidwho-381721

RESUMO

The novel coronavirus disease 2019 (COVID-19) has grown to be a global public health emergency since patients were first detected in Wuhan, China. Thus far, no specific drugs or vaccines are available to cure the patients with COVID-19 infection. The immune system and inflammation are proposed to play a central role in COVID-19 pathogenesis. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. Intravenous infusion of MSCs has shown promising results in COVID-19 treatment. Here, we report a case of a severe COVID-19 patient treated with human umbilical cord Wharton's jelly-derived MSCs (hWJCs) from a healthy donor in Liaocheng People's Hospital, China, from February 24, 2020. The pulmonary function and symptoms of the patient with COVID-19 pneumonia was significantly improved in 2 days after hWJC transplantation, and recovered and discharged in 7 days after treatment. After treatment, the percentage and counts of lymphocyte subsets (CD3+, CD4+, and CD8+ T cell) were increased, and the level of IL-6, TNF-α, and C-reactive protein is significantly decreased after hWJC treatment. Thus, the intravenous transplantation of hWJCs was safe and effective for the treatment of patients with COVID-19 pneumonia, especially for the patients in a critically severe condition. This report highlights the potential of hWJC infusions as an effective treatment for COVID-19 pneumonia.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Pneumonia Viral/terapia , Betacoronavirus/genética , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Humanos , Imunomodulação , Infusões Intravenosas , Interleucina-6/sangue , Interleucina-6/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/virologia , Masculino , Células-Tronco Mesenquimais/imunologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Cordão Umbilical/citologia , Cordão Umbilical/imunologia , Geleia de Wharton/citologia , Geleia de Wharton/imunologia
19.
Clin Exp Immunol ; 201(1): 76-84, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-184034

RESUMO

Effective laboratory markers for the estimation of disease severity and predicting the clinical progression of coronavirus disease-2019 (COVID-19) is urgently needed. Laboratory tests, including blood routine, cytokine profiles and infection markers, were collected from 389 confirmed COVID-19 patients. The included patients were classified into mild (n = 168), severe (n = 169) and critical groups (n = 52). The leukocytes, neutrophils, infection biomarkers [such as C-reactive protein (CRP), procalcitonin (PCT) and ferritin] and the concentrations of cytokines [interleukin (IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α] were significantly increased, while lymphocytes were significantly decreased with increased severity of illness. The amount of IL-2R was positively correlated with the other cytokines and negatively correlated with lymphocyte number. The ratio of IL-2R to lymphocytes was found to be remarkably increased in severe and critical patients. IL-2R/lymphocytes were superior compared with other markers for the identification of COVID-19 with critical illness, not only from mild but also from severe illness. Moreover, the cytokine profiles and IL-2R/lymphocytes were significantly decreased in recovered patients, but further increased in disease-deteriorated patients, which might be correlated with the outcome of COVID-19. Lymphopenia and increased levels of cytokines were closely associated with disease severity. The IL-2R/lymphocyte was a prominent biomarker for early identification of severe COVID-19 and predicting the clinical progression of the disease.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Subunidade alfa de Receptor de Interleucina-2/sangue , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Linfócitos T/virologia , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/imunologia , Biomarcadores/sangue , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , China/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Progressão da Doença , Feminino , Ferritinas/sangue , Ferritinas/imunologia , Humanos , Interleucina-10/sangue , Interleucina-10/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-8/sangue , Interleucina-8/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pró-Calcitonina/sangue , Pró-Calcitonina/imunologia , Prognóstico , Índice de Gravidade de Doença , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
20.
Stem Cell Res Ther ; 11(1): 207, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32460839

RESUMO

The novel coronavirus disease 2019 (COVID-19) has grown to be a global public health emergency since patients were first detected in Wuhan, China. Thus far, no specific drugs or vaccines are available to cure the patients with COVID-19 infection. The immune system and inflammation are proposed to play a central role in COVID-19 pathogenesis. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. Intravenous infusion of MSCs has shown promising results in COVID-19 treatment. Here, we report a case of a severe COVID-19 patient treated with human umbilical cord Wharton's jelly-derived MSCs (hWJCs) from a healthy donor in Liaocheng People's Hospital, China, from February 24, 2020. The pulmonary function and symptoms of the patient with COVID-19 pneumonia was significantly improved in 2 days after hWJC transplantation, and recovered and discharged in 7 days after treatment. After treatment, the percentage and counts of lymphocyte subsets (CD3+, CD4+, and CD8+ T cell) were increased, and the level of IL-6, TNF-α, and C-reactive protein is significantly decreased after hWJC treatment. Thus, the intravenous transplantation of hWJCs was safe and effective for the treatment of patients with COVID-19 pneumonia, especially for the patients in a critically severe condition. This report highlights the potential of hWJC infusions as an effective treatment for COVID-19 pneumonia.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Pneumonia Viral/terapia , Betacoronavirus/genética , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Humanos , Imunomodulação , Infusões Intravenosas , Interleucina-6/sangue , Interleucina-6/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/virologia , Masculino , Células-Tronco Mesenquimais/imunologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Cordão Umbilical/citologia , Cordão Umbilical/imunologia , Geleia de Wharton/citologia , Geleia de Wharton/imunologia
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