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1.
PLoS Pathog ; 16(9): e1008854, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956405

RESUMO

Aspergillus fumigatus is an opportunistic fungal pathogen of immunocompromised patient populations. Mortality is thought to be context-specific and occurs via both enhanced fungal growth and immunopathogenesis. NLRX1 is a negative regulator of immune signaling and metabolic pathways implicated in host responses to microbes, cancers, and autoimmune diseases. Our study indicates loss of Nlrx1 results in enhanced fungal burden, pulmonary inflammation, immune cell recruitment, and mortality across immuno-suppressed and immuno-competent models of IPA using two clinically derived isolates (AF293, CEA10). We observed that the heightened mortality is due to enhanced recruitment of CD103+ dendritic cells (DCs) that produce elevated amounts of IL-4 resulting in a detrimental Th2-mediated immune response. Adoptive transfer of Nlrx1-/- CD103+ DCs in neutropenic NRG mice results in enhanced mortality that can be ablated using IL-4 neutralizing antibodies. In vitro analysis of CD103+ DCs indicates loss of Nlrx1 results in enhanced IL-4 production via elevated activation of the JNK/JunB pathways. Interestingly, loss of Nlrx1 also results in enhanced recruitment of monocytes and neutrophils. Chimeras of irradiated Nlrx1-/- mice reconstituted with wild type bone marrow have enhanced neutrophil recruitment and survival during models of IPA. This enhanced immune cell recruitment in the absence of Nlrx1 is mediated by excessive production of CXCL8/IL-8 family of chemokines and IL-6 via early and enhanced activation of P38 in response to A. fumigatus conidia as shown in BEAS-2B airway epithelial cells. In summary, our results point strongly towards the cell-specific and contextual function of Nlrx1 during invasive pulmonary aspergillosis and may lead to novel therapeutics to reduce Th2 responses by CD103+ DCs or heightened recruitment of neutrophils.


Assuntos
Aspergillus fumigatus/imunologia , Células Dendríticas/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Proteínas Mitocondriais/imunologia , Aspergilose Pulmonar/imunologia , Células Th2/imunologia , Animais , Linhagem Celular , Citocinas/genética , Citocinas/imunologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/imunologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/genética , Neutrófilos/imunologia , Neutrófilos/patologia , Aspergilose Pulmonar/genética , Aspergilose Pulmonar/patologia , Células Th2/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
3.
Nat Commun ; 11(1): 4387, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873795

RESUMO

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils.


Assuntos
Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Mamárias Animais/imunologia , Neutropenia/prevenção & controle , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral/transplante , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Injeções Intravenosas , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/sangue , Neoplasias Mamárias Animais/complicações , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos NOD , Neutropenia/sangue , Neutropenia/etiologia , Neutropenia/imunologia , Neutrófilos/efeitos dos fármacos , Cultura Primária de Células
4.
Sci Rep ; 10(1): 15838, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985562

RESUMO

The coronavirus disease 2019 (COVID-19) has been spreading worldwide. Severe cases quickly progressed with unfavorable outcomes. We aim to investigate the clinical features of COVID-19 and identify the risk factors associated with its progression. Data of confirmed SARS-CoV-2-infected patients and healthy participants were collected. Thirty-seven healthy people and 79 confirmed patients, which include 48 severe patients and 31 mild patients, were recruited. COVID-19 patients presented with dysregulated immune response (decreased T, B, and NK cells and increased inflammatory cytokines). Also, they were found to have increased levels of white blood cell, neutrophil count, and D-dimer in severe cases. Moreover, lymphocyte, CD4+ T cell, CD8+ T cell, NK cell, and B cell counts were lower in the severe group. Multivariate logistic regression analysis showed that CD4+ cell count, neutrophil-to-lymphocyte ratio (NLR) and D-dimer were risk factors for severe cases. Both CT score and clinical pulmonary infection score (CPIS) were associated with disease severity. The receiver operating characteristic (ROC) curve analysis has shown that all these parameters and scores had quite a high predictive value. Immune dysfunction plays critical roles in disease progression. Early and constant surveillance of complete blood cell count, T lymphocyte subsets, coagulation function, CT scan and CPIS was recommended for early screening of severe cases.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Fenômenos do Sistema Imunológico/fisiologia , Pneumonia Viral/imunologia , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
5.
PLoS Pathog ; 16(8): e1008741, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32750085

RESUMO

Aspergillus fumigatus is an opportunistic mold that infects patients who are immunocompromised or have chronic lung disease, causing significant morbidity and mortality in these populations. While the factors governing the host response to A. fumigatus remain poorly defined, neutrophil recruitment to the site of infection is critical to clear the fungus. Galectin-3 is a mammalian ß-galactose-binding lectin with both antimicrobial and immunomodulatory activities, however the role of galectin-3 in the defense against molds has not been studied. Here we show that galectin-3 expression is markedly up-regulated in mice and humans with pulmonary aspergillosis. Galectin-3 deficient mice displayed increased fungal burden and higher mortality during pulmonary infection. In contrast to previous reports with pathogenic yeast, galectin-3 exhibited no antifungal activity against A. fumigatus in vitro. Galectin-3 deficient mice exhibited fewer neutrophils in their airways during infection, despite normal numbers of total lung neutrophils. Intravital imaging studies confirmed that galectin-3 was required for normal neutrophil migration to the airspaces during fungal infection. Adoptive transfer experiments demonstrated that stromal rather than neutrophil-intrinsic galectin-3 was necessary for normal neutrophil entry into the airspaces. Live cell imaging studies revealed that extracellular galectin-3 directly increases neutrophil motility. Taken together, these data demonstrate that extracellular galectin-3 facilitates recruitment of neutrophils to the site of A. fumigatus infection, and reveals a novel role for galectin-3 in host defense against fungal infections.


Assuntos
Aspergilose/imunologia , Aspergillus fumigatus/fisiologia , Galectina 3/imunologia , Pulmão/microbiologia , Neutrófilos/citologia , Animais , Aspergilose/genética , Aspergilose/microbiologia , Aspergilose/fisiopatologia , Aspergillus fumigatus/genética , Movimento Celular , Feminino , Galectina 3/genética , Humanos , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia
6.
Clin Immunol ; 219: 108555, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32771488

RESUMO

Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19.


Assuntos
Lesão Renal Aguda/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/patogenicidade , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Lesão Renal Aguda/complicações , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/virologia , Adulto , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Ativação do Complemento/efeitos dos fármacos , Complemento C4b/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Imunidade Humoral/efeitos dos fármacos , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Pandemias , Fragmentos de Peptídeos/antagonistas & inibidores , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia
7.
Ann Hematol ; 99(10): 2265-2277, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32803313

RESUMO

ß-Thalassemia is an inherited single gene disorder related to reduced synthesis of the ß-globin chain of hemoglobin. Patients with ß-thalassemia present variable clinical severity ranging from asymptomatic trait to severe transfusion-dependent anemia and multiple organs complications. Moreover, multiple immune abnormalities are a major concern in ß-thalassemia patients. Aberrant neutrophil effector function plays a pivotal role in infection susceptibility in these patients. In severe and persistent inflammation, immature neutrophils are released from the bone marrow and are functionally different compared with mature ones. Despite some abnormalities reported for thalassemia patient's immune system, few data exist on the characterization of human neutrophils in ß-thalassemia. The aim of this study was to investigate the phenotype and function of circulating neutrophil subsets in patients with ß-thalassemia major and with ß-thalassemia intermedia divided in transfusion-dependent and non-transfusion-dependent. By the use of immunochemical and cytofluorimetric analyses, we observed that patients' CD16+ neutrophils exhibit abnormalities in their phenotype and functions and the abnormalities vary according to the clinical form of the disease and to the neutrophil subset (CD16bright and CD16dim). Abnormalities include altered surface expression of the innate immune receptor CD45, Toll-like receptor 4, and CD32, reduced ability to produce an oxidative burst, and elevated levels of membrane lipid peroxidation, especially in patients with a more severe form of the disease. Overall, our results indicating the occurrence of an immuno-senescent phenotype on circulating neutrophils from thalassemia patients suggest the usefulness of neutrophil feature assessment as a tool for better clinical management of ß-thalassemia.


Assuntos
Neutrófilos/imunologia , Talassemia beta/sangue , Adulto , Antígenos CD/sangue , Transfusão de Componentes Sanguíneos , Senescência Celular , Terapia por Quelação , Feminino , Ferritinas/sangue , Humanos , Imunofenotipagem , Quelantes de Ferro/uso terapêutico , Contagem de Leucócitos , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Ativação de Neutrófilo , Neutrófilos/química , Neutrófilos/classificação , Explosão Respiratória , Esplenectomia , Receptor 4 Toll-Like/sangue , Adulto Jovem , Talassemia beta/imunologia , Talassemia beta/terapia
8.
Science ; 369(6506)2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820093

RESUMO

In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening complications, the underlying mechanisms remain unknown. Here, we used orthogonal approaches in human patients with proliferative diabetic retinopathy and a mouse model of ischemic retinopathies to identify an unconventional role for neutrophils in vascular remodeling during late-stage sterile inflammation. Senescent vasculature released a secretome that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). NETs ultimately cleared diseased endothelial cells and remodeled unhealthy vessels. Genetic or pharmacological inhibition of NETosis prevented the regression of senescent vessels and prolonged disease. Thus, clearance of senescent retinal blood vessels leads to reparative vascular remodeling.


Assuntos
Envelhecimento/patologia , Retinopatia Diabética/patologia , Armadilhas Extracelulares/imunologia , Vasos Retinianos/patologia , Animais , Senescência Celular , Retinopatia Diabética/imunologia , Modelos Animais de Doenças , Células Endoteliais/imunologia , Células Endoteliais/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Vasos Retinianos/imunologia
9.
PLoS Pathog ; 16(8): e1008414, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776983

RESUMO

The host innate immune system has developed elegant processes for the detection and clearance of invasive fungal pathogens. These strategies may also aid in the spread of pathogens in vivo, although technical limitations have previously hindered our ability to view the host innate immune and endothelial cells to probe their roles in spreading disease. Here, we have leveraged zebrafish larvae as a model to view the interactions of these host processes with the fungal pathogen Candida albicans in vivo. We examined three potential host-mediated mechanisms of fungal spread: movement inside phagocytes in a "Trojan Horse" mechanism, inflammation-assisted spread, and endothelial barrier passage. Utilizing both chemical and genetic tools, we systematically tested the loss of neutrophils and macrophages and the loss of blood flow on yeast cell spread. Both neutrophils and macrophages respond to yeast-locked and wild type C. albicans in our model and time-lapse imaging revealed that macrophages can support yeast spread in a "Trojan Horse" mechanism. Surprisingly, loss of immune cells or inflammation does not alter dissemination dynamics. On the other hand, when blood flow is blocked, yeast can cross into blood vessels but they are limited in how far they travel. Blockade of both phagocytes and circulation reduces rates of dissemination and significantly limits the distance of fungal spread from the infection site. Together, this data suggests a redundant two-step process whereby (1) yeast cross the endothelium inside phagocytes or via direct uptake, and then (2) they utilize blood flow or phagocytes to travel to distant sites.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Células Endoteliais/imunologia , Interações Hospedeiro-Patógeno/imunologia , Neutrófilos/imunologia , Fagócitos/imunologia , Peixe-Zebra/microbiologia , Animais , Candidíase/microbiologia , Larva , Macrófagos/imunologia , Macrófagos/microbiologia , Neutrófilos/microbiologia , Fagócitos/microbiologia
10.
PLoS Pathog ; 16(8): e1008230, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797076

RESUMO

Neutrophil extracellular traps (NETs) evolved as a unique effector mechanism contributing to resistance against infection that can also promote tissue damage in inflammatory conditions. Malaria infection can trigger NET release, but the mechanisms and consequences of NET formation in this context remain poorly characterized. Here we show that patients suffering from severe malaria had increased amounts of circulating DNA and increased neutrophil elastase (NE) levels in plasma. We used cultured erythrocytes and isolated human neutrophils to show that Plasmodium-infected red blood cells release macrophage migration inhibitory factor (MIF), which in turn caused NET formation by neutrophils in a mechanism dependent on the C-X-C chemokine receptor type 4 (CXCR4). NET production was dependent on histone citrullination by peptidyl arginine deiminase-4 (PAD4) and independent of reactive oxygen species (ROS), myeloperoxidase (MPO) or NE. In vitro, NETs functioned to restrain parasite dissemination in a mechanism dependent on MPO and NE activities. Finally, C57/B6 mice infected with P. berghei ANKA, a well-established model of cerebral malaria, presented high amounts of circulating DNA, while treatment with DNAse increased parasitemia and accelerated mortality, indicating a role for NETs in resistance against Plasmodium infection.


Assuntos
Eritrócitos/imunologia , Armadilhas Extracelulares/imunologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Malária/imunologia , Neutrófilos/imunologia , Plasmodium/imunologia , Receptores CXCR4/metabolismo , Animais , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/parasitologia , Humanos , Malária/metabolismo , Malária/parasitologia , Malária/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Neutrófilos/parasitologia , Parasitemia/imunologia , Parasitemia/metabolismo , Parasitemia/parasitologia , Parasitemia/patologia
11.
Front Immunol ; 11: 1692, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754162

RESUMO

Coronavirus-induced disease-2019 (COVID-19) continues to cause significant morbidity and mortality worldwide. While studies on SARS-CoV-2 effects 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 outlines what is the reported literature thus far on the effect of virus on NK cells known to kill virally infected cells. It also underscores the necessity for the future comprehensive studies of NK cells in SARS-CoV-2 infected individuals and animal models to better understand the role and significance of reported NK cell depletion and functional inactivation in disease morbidity and mortality, in hope to design effective therapeutic interventions for the disease.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Adulto , Idoso , Animais , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Citocinas/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/virologia
12.
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
13.
Infect Dis Poverty ; 9(1): 108, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32746940

RESUMO

BACKGROUND: The number of coronavirus disease 2019 (COVID-19) cases has rapidly increased all over the world. Specific information about immunity in non-survivors with COVID-19 is scarce. This study aimed to analyse the clinical characteristics and abnormal immunity of the confirmed COVID-19 non-survivors. METHODS: In this single-centered, retrospective, observational study, we enrolled 125 patients with COVID-19 who were died between January 13 and March 4, 2020 in Renmin Hospital of Wuhan University. A total of 414 randomly recruited patients with confirmed COVID-19 who were discharged from the same hospital during the same period served as control. The demographic, clinical characteristics and laboratory findings at admission, and treatment used in these patients were collected. The immunity-related risk factors associated with in-hospital death were tested by logistic regression models and Receiver Operating Characteristic (ROC) curve. RESULTS: Non-survivors (70 years, IQR: 61.5-80) were significantly older than survivors (54 years, IQR: 37-65) (P <  0.001). 56.8% of non-survivors was male. Nearly half of the patients (44.9%) had chronic medical illness. In non-survivors, hypertension (49.6%) was the most common comorbidity, followed by diabetes (20.0%) and coronary heart disease (16.0%). The common signs and symptoms at admission of non-survivors were fever (88%), followed by cough (64.8%), dyspnea (62.4%), fatigue (62.4%) and chest tightness (58.4%). Compared with survivors, non-survivors had higher white blood cell (WBC) count (7.85 vs 5.07 × 109/L), more elevated neutrophil count (6.41 vs 3.08 × 109/L), smaller lymphocyte count (0.69 vs 1.20 × 109/L) and lower platelet count (172 vs 211 × 109/L), raised concentrations of procalcitonin (0.21 vs 0.06 ng/mL) and CRP (70.5 vs 7.2 mg/L) (P < 0.001). This was accompanied with significantly decreased levels of CD3+ T cells (277 vs 814 cells/µl), CD4+ T cells (172 vs 473 cells/µl), CD8+ T cells (84 vs 262.5 cells/µl, P < 0.001), CD19+ T cells (88 vs 141 cells/µl) and CD16+ 56+ T cells (79 vs 128.5 cells/µl) (P < 0.001). The concentrations of immunoglobulins (Ig) G (13.30 vs 11.95 g/L), IgA (2.54 vs 2.21 g/L), and IgE (71.30 vs 42.25 IU/ml) were increased, whereas the levels of complement proteins (C)3 (0.89 vs 0.99 g/L) and C4 (0.22 vs 0.24 g/L) were decreased in non-survivors when compared with survivors (all P < 0.05). The non-survivors presented lower levels of oximetry saturation (90 vs 97%) at rest and lactate (2.40 vs 1.90 mmol/L) (P < 0.001). Old age, comorbidity of malignant tumor, neutrophilia, lymphocytopenia, low CD4+ T cells, decreased C3, and low oximetry saturation were the risk factors of death in patients with confirmed COVID-19. The frequency of CD4+ T cells positively correlated with the numbers of lymphocytes (r = 0.787) and the level of oximetry saturation (r = 0.295), Whereas CD4+ T cells were negatively correlated with age (r =-0.323) and the numbers of neutrophils (r = - 0.244) (all P < 0.001). CONCLUSIONS: Abnormal cellular immunity and humoral immunity were key features of non-survivors with COVID-19. Neutrophilia, lymphocytopenia, low CD4+ T cells, and decreased C3 were immunity-related risk factors predicting mortality of patients with COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/isolamento & purificação , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , China/epidemiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Contagem de Leucócitos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/epidemiologia , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
14.
Adv Biol Regul ; 77: 100741, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773102

RESUMO

Pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses an unprecedented challenge to healthcare systems due to the lack of a vaccine and specific treatment options. Accordingly, there is an urgent need to understand precisely the pathogenic mechanisms underlying this multifaceted disease. There is increasing evidence that the immune system reacts insufficiently to SARS-CoV-2 and thus contributes to organ damage and to lethality. In this review, we suggest that the overwhelming production of reactive oxygen species (ROS) resulting in oxidative stress is a major cause of local or systemic tissue damage that leads to severe COVID-19. It increases the formation of neutrophil extracellular traps (NETs) and suppresses the adaptive arm of the immune system, i.e. T cells that are necessary to kill virus-infected cells. This creates a vicious cycle that prevents a specific immune response against SARS-CoV-2. The key role of oxidative stress in the pathogenesis of severe COVID-19 implies that therapeutic counterbalancing of ROS by antioxidants such as vitamin C or NAC and/or by antagonizing ROS production by cells of the mononuclear phagocyte system (MPS) and neutrophil granulocytes and/or by blocking of TNF-α can prevent COVID-19 from becoming severe. Controlled clinical trials and preclinical models of COVID-19 are needed to evaluate this hypothesis.


Assuntos
Antioxidantes/uso terapêutico , Infecções por Coronavirus/epidemiologia , Armadilhas Extracelulares/imunologia , Linfopenia/epidemiologia , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Acetilcisteína/uso terapêutico , Ácido Ascórbico/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Linfopenia/tratamento farmacológico , Linfopenia/imunologia , Linfopenia/virologia , NF-kappa B/genética , NF-kappa B/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/virologia , Estresse Oxidativo/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
15.
Mol Immunol ; 125: 51-62, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32645550

RESUMO

Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of TBK1 and interferon pathway and the expression of SOCS3 is closely correlated with symptoms of influenza patients. However, whether deletion of Socs3 in the lung epithelial cells would affect influenza lung replication and inflammation in vivo is unknown. To test this, we approached the influenza infected Socs3f/f and SpcCre.Socs3f/f mice. We first found that knockdown of Socs3 in lung epithelial cells reduced influenza replication. However, in the in vivo study, there was a reduction of SOCS3 in the influenza-infected neutrophils coincided with an increase of SOCS3 in the CD45-CD326+ lung epithelial cells in PR8-infected SpcCre.Socs3f/f mice. SOCS3-deficient neutrophils expressed higher levels of IL-17 that enhanced chemokine expression in the lung epithelial cells. Lung SOCS3-dificient epithelial cells increased expression of GM-CSF and PGE2 which promoted SpcCre.Socs3f/f neutrophils to yield SOCS3. SpcCre.Socs3f/f lung epithelial cells internalized SOCS3 released from GM-CSF + PGE2-stimulated SpcCre.Socs3f/f neutrophils, which could boost influenza replication in the lung epithelial cells. Thus, in the in vivo study, deletion of SOCS3 from lung epithelium could be nullified by the uptake from SOCS3 from infiltrated neutrophils. In addition, deletion of Socs3 from myeloid cells reduced lung influenza infection, but increased lung inflammation. Taken together, deletion of SOCS3 could suppress influenza replication, but intracellular SOCS3 communication between neutrophils and lung epithelial cells confounds this effect.


Assuntos
Células Epiteliais Alveolares/imunologia , Neutrófilos/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções Respiratórias/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/imunologia , Células Epiteliais Alveolares/metabolismo , Animais , Vírus da Influenza A , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Infecções Respiratórias/metabolismo , Infecções Respiratórias/virologia , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
16.
Mol Immunol ; 125: 95-103, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659598

RESUMO

Myeloid-derived suppressor cells (MDSCs) are classified into polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. The predominant subtype of MDSCs in hepatocellular carcinoma (HCC) is still elusive. The spleen is the largest immune organ in the body and is the origin of many cells. It is still unknown whether the spleen is the origin of MDSCs. In this study, we investigated the expression, origin and mobilization of the predominant MDSC subtype in H22 orthotopic hepatoma mice. Compared with M-MDSCs, PMN-MDSCs were increased and dominant in the spleen, peripheral blood and tumor tissues. Splenectomy could decrease the percentages of PMN-MDSCs in the peripheral blood and tumor tissues, increase the frequencies of NK cells in the peripheral blood and CD3+CD4+T, CD3+CD8+T, NK and NKT cells in the tumor tissues, reduce the tumor weight and the amounts of ascites, and prolong survival time in hepatoma mice. The levels of chemokine (CC motif) ligand 9 (CCL9) and chemokine (CC motif) ligand 2 (CCL2) were elevated in the peripheral blood of tumor-bearing (TB) mice, and their receptors CCR1 and CCR2 were expressed on spleen PMN-MDSCs. Migration assay showed that CCL2 and CCL9 could attract spleen PMN-MDSCs in vitro. These results indicate that PMN-MDSCs were increased and dominant in orthotopic H22 hepatoma mice, the spleen contributed to the increase of PMN-MDSCs, and PMN-MDSCs could be mobilized from the spleen to the peripheral blood by CCL9 and CCL2, thus facilitated tumor growth.


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , Baço/imunologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Camundongos , Evasão Tumoral/imunologia
18.
Ther Adv Respir Dis ; 14: 1753466620942129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32684101

RESUMO

BACKGROUND: In December of 2019, coronavirus disease 2019 (Covid-19) was reported in Wuhan, China, and has now rapidly swept around the world. Much research has been carried out since the outbreak, but few studies have focused on the dysfunction of the adaptive immunity. METHODS: In this retrospective and multi-center study, 373 patients with laboratory-confirmed COVID-19 from Shanghai Public Health Clinical Center and Affiliated Hospital of Putian University were recruited. Demographic, clinical, radiological features, and laboratory data were recorded and analyzed at admission and at discharge. Results of immunological tests were followed up until the patients were discharged. RESULTS: Of the 373 patients with COVID-19 pneumonia, 322 were in the non-severe group and 51 were in the severe group. Number of T cells, CD4+ and CD8+ T cells, and total lymphocytes declined remarkably upon admission and elevated when the patients were discharged. At admission, counts of total lymphocytes, T cells, CD4+ and CD8+ T cells, and levels of C3 and C4 in the severe group were lower than those in the non-severe group, whereas the neutrophil to lymphocyte ratio (NLR) was higher in the severe group. Counts of T cells, CD4+ and CD8+ T cells, and total lymphocytes were negatively correlated with lactate dehydrogenase and C-reactive protein. CONCLUSION: COVID-19 might target adaptive immunity and cause a decrease in lymphocytes, especially T cells and subsets. Physicians should pay close attention to the adaptive immunity of patients upon admission. Monitoring NLR, T lymphocytes, and subsets would help physicians with the proper diagnosis and treatment of COVID-19.The reviews of this paper are available via the supplemental material section.


Assuntos
Imunidade Adaptativa/imunologia , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Estudos Retrospectivos , Índice de Gravidade de Doença
19.
Mol Immunol ; 124: 211-217, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32603960

RESUMO

The primary immune response against Staphylococcus aureus is mediated by neutrophils. In response to S. aureus and its proteins, neutrophil shows two different kinds of NETosis, viz. suicidal and vesicular NETosis. Glucose is the major energy source of neutrophils for performing NETosis. However, NETosis was found altered in response to high glucose levels. Growth of S. aureus was also found modulated in response to high glucose and they behave differently at different glucose levels. This work was attempted to study NET release in response to S. aureus cell-free culture supernatant at different glucose concentrations. Freshly isolated neutrophils were treated with different concentrations of glucose along with S. aureus cell-free culture supernatant and were analyzed for neutrophil extracellular trap formation, ROS production, and peptidylarginine deiminase 4 activities. Influence of calcium on NETosis was analyzed using calcium chelator (EDTA) and calcium inhibitor (TMB-8). With increasing glucose levels, NET release in response to S. aureus cell-free culture supernatant was increased. Oxidant level was also increased dose-dependently with increasing concentrations of glucose. At very high glucose concentrations (> 15 mM), vesicular NETosis was predominantly observed. At these glucose concentrations, peptidylarginine deiminase activity was found to be decreased. Furthermore, calcium quenching in the medium facilitated vesicular mode of NET release. In conclusion, calcium depletion occurring at high glucose concentrations can reduce peptidylarginine deiminase 4 activity and can thereby promote the vesicular NET release.


Assuntos
Cálcio/metabolismo , Armadilhas Extracelulares/metabolismo , Glucose/metabolismo , Neutrófilos/imunologia , Staphylococcus aureus/imunologia , Células Cultivadas , Armadilhas Extracelulares/imunologia , Humanos , Vesículas Secretórias/metabolismo , Infecções Estafilocócicas/imunologia
20.
Sci Immunol ; 5(49)2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669287

RESUMO

Although critical illness has been associated with SARS-CoV-2-induced hyperinflammation, the immune correlates of severe COVID-19 remain unclear. Here, we comprehensively analyzed peripheral blood immune perturbations in 42 SARS-CoV-2 infected and recovered individuals. We identified extensive induction and activation of multiple immune lineages, including T cell activation, oligoclonal plasmablast expansion, and Fc and trafficking receptor modulation on innate lymphocytes and granulocytes, that distinguished severe COVID-19 cases from healthy donors or SARS-CoV-2-recovered or moderate severity patients. We found the neutrophil to lymphocyte ratio to be a prognostic biomarker of disease severity and organ failure. Our findings demonstrate broad innate and adaptive leukocyte perturbations that distinguish dysregulated host responses in severe SARS-CoV-2 infection and warrant therapeutic investigation.


Assuntos
Subpopulações de Linfócitos B/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Idoso , Seleção Clonal Mediada por Antígeno/imunologia , Infecções por Coronavirus/patologia , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia
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