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1.
EClinicalMedicine ; 40: 101099, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34490415

RESUMO

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. Methods: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS). Findings: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles. Interpretation: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. Funding: Funded by Roche Sequencing Solutions, Inc.

2.
Infection ; 49(4): 757-762, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33825125

RESUMO

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.


Assuntos
COVID-19/imunologia , Monócitos/imunologia , SARS-CoV-2/fisiologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/sangue , Idoso , Feminino , Hospitalização , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/biossíntese , Regulação para Cima
3.
Eur J Microbiol Immunol (Bp) ; 8(4): 128-134, 2018 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-30719329

RESUMO

In chronic obstructive pulmonary disease (COPD), acute exacerbations and emphysema development are characteristics for disease pathology. COPD is complicated by infectious exacerbations with acute worsening of respiratory symptoms with Moraxella catarrhalis as one of the most frequent pathogens. Although cigarette smoke (CS) is the primary risk factor, additional molecular mechanisms for emphysema development induced by bacterial infections are incompletely understood. We investigated the impact of M. catarrhalis on emphysema development in CS exposed mice and asked whether an additional infection would induce a solubilization of pro-apoptotic and pro-inflammatory endothelial monocyte-activating-protein-2 (EMAPII) to exert its activities in the pulmonary microvas-culature and other parts of the lungs not exposed directly to CS. Mice were exposed to smoke (6 or 9 months) and/or infected with M. catarrhalis. Lungs, bronchoalveolar lavage fluid (BALF), and plasma were analyzed. CS exposure reduced ciliated area, caused rarefaction of the lungs, and induced apoptosis. EMAPII was increased independent of prior smoke exposure in BALF of infected mice. Importantly, acute M. catarrhalis infection increased release of matrixmetalloproteases-9 and -12, which are involved in emphysema development and comprise a mechanism of EMAPII release. Our data suggest that acute M. catarrhalis infection represents an independent risk factor for emphysema development in smoke-exposed mice.

4.
Exp Hematol ; 44(10): 917-23, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27403536

RESUMO

Acute and chronic graft-versus-host-diseases (aGVHD and cGVHD, respectively) are serious complications after hematopoietic stem cell transplantation (HSCT), impairing survival and quality of life. Because the underlying pathomechanism of GVHD is still poorly understood, we investigated the novel inflammatory marker Pentraxin-3 (PTX3) for its potential role in acute and chronic GVHD compared with autologous HSCT and healthy individuals. We collected plasma samples from patients undergoing autologous (n = 12) and allogeneic (n = 28) HSCT and from healthy individuals (n = 15) throughout 7 days before and up to 1 year after HSCT. PTX3 levels in patients with aGVHD were significantly higher (36.4 ± 23.6 ng/mL) than in allogeneic patients without aGVHD (10.4 ± 4.4 ng/mL, p = 0.0001), autologous controls (11.4 ± 6.7 ng/mL, p = 0.001), or healthy individuals (1.9 ± 0.6 ng/mL, p < 0.001). PTX3 levels in patients with cGVHD (13.6 ± 6.3 ng/mL) were significantly lower than in allogeneic patients without cGVHD (25.1 ± 13.8 ng/mL, p = 0.04) and higher than in autologous controls (8.9 ± 7.8 ng/mL, p = 0.07) and healthy individuals (1.9 ± 0.6 ng/mL, p < 0.001). Severity of aGVHD and cGVHD correlated with PTX3 levels. Rising PTX3 levels after HSCT indicated unfavorable outcome. We show that PTX3 levels correlate with the severity of aGVHD, cGVHD, and-with reservations-survival in patients undergoing allogeneic HSCT.


Assuntos
Proteína C-Reativa , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Componente Amiloide P Sérico , Doença Aguda , Adulto , Biomarcadores , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante Autólogo , Transplante Homólogo
5.
Am J Physiol Lung Cell Mol Physiol ; 309(3): L250-61, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26047639

RESUMO

In patients with chronic obstructive pulmonary disease (COPD), Moraxella catarrhalis infection of the lower airways is associated with chronic colonization and inflammation during stable disease and acute exacerbations. Chronic smoke exposure induces chronic inflammation and impairs mucociliary clearance, thus contributing to bacterial colonization of the lower airways in COPD patients. The human-specific carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 5, expressed in human airways, has been shown to contribute to epithelial colonization of CEACAM-binding pathogens. To investigate the impact of CEACAM5 expression on pulmonary M. catarrhalis colonization, we infected mice transgenic for human CEACAM5 (hCEACAM5) and wild type mice intratracheally with M. catarrhalis with or without preceding smoke exposure and analyzed bacterial colonization and local and systemic inflammation. Our results show that airway infection with M. catarrhalis accelerated acute local but not systemic inflammation, albeit independent of hCEACAM5 expression. Long-term smoke exposure alone or prior to M. catarrhalis infection did not contribute to increased local or systemic inflammation. No difference was found in pulmonary clearance of M. catarrhalis in hCEACAM5-transgenic mice compared with wild-type mice. Smoke exposure neither altered time nor extent of persistence of M. catarrhalis in the lungs of both genotypes. In conclusion, M. catarrhalis induced a local acute immune response in murine airways. Neither hCEACAM5 expression nor chronic smoke exposure nor a combination of both was sufficient as prerequisites for the establishment of chronic M. catarrhalis colonization. Our results demonstrate the difficulties in mirroring conditions of chronic airways colonization of M. catarrhalis in a murine model.


Assuntos
Antígeno Carcinoembrionário/metabolismo , Pulmão/metabolismo , Moraxella catarrhalis/imunologia , Infecções por Moraxellaceae/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Animais , Antígeno Carcinoembrionário/genética , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infecções por Moraxellaceae/metabolismo , Infecções por Moraxellaceae/microbiologia , Depuração Mucociliar , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/imunologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Fumar/imunologia , Fumar/metabolismo
6.
Am J Respir Cell Mol Biol ; 53(4): 544-54, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25756955

RESUMO

In severe pneumococcal pneumonia, the delicate balance between a robust inflammatory response necessary to kill bacteria and the loss of organ function determines the outcome of disease. In this study, we tested the hypothesis that Krueppel-like factor (KLF) 4 may counter-regulate Streptococcus pneumoniae-related human lung epithelial cell activation using the potent proinflammatory chemokine IL-8 as a model molecule. Pneumococci induced KLF4 expression in human lung, in primary human bronchial epithelial cells, and in the lung epithelial cell line BEAS-2B. Whereas proinflammatory cell activation depends mainly on the classical Toll-like receptor 2-mitogen-activated protein kinase or phosphatidylinositide 3-kinase and NF-κB pathways, the induction of KLF4 occurred independently of these molecules but relied, in general, on tyrosine kinase activation and, in part, on the src kinase family member yamaguchi sarcoma viral oncogene homolog (yes) 1. The up-regulation of KLF4 depended on the activity of the main pneumococcal autolysin LytA. KLF4 overexpression suppressed S. pneumoniae-induced NF-κB and IL-8 reporter gene activation and release, whereas small interfering RNA-mediated silencing of KLF4 or yes1 kinase led to an increase in IL-8 release. The KLF4-dependent down-regulation of NF-κB luciferase activity could be rescued by the overexpression of the histone acetylase p300/cAMP response element-binding protein-associated factor. In conclusion, KLF4 acts as a counter-regulatory transcription factor in pneumococci-related proinflammatory activation of lung epithelial cells, thereby potentially preventing lung hyperinflammation and subsequent organ failure.


Assuntos
Proteínas de Bactérias/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , N-Acetil-Muramil-L-Alanina Amidase/fisiologia , Pneumonia Pneumocócica/metabolismo , Mucosa Respiratória/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/imunologia , Interações Hospedeiro-Patógeno , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/microbiologia , Regiões Promotoras Genéticas , Mucosa Respiratória/microbiologia , Transdução de Sinais , Streptococcus pneumoniae/enzimologia , Receptor Toll-Like 9/metabolismo
7.
J Vasc Res ; 52(4): 279-88, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26890419

RESUMO

Pulmonary vascular hyperresponsiveness is a main characteristic of pulmonary arterial hypertension (PAH). In PAH patients, elevated levels of the vasoconstrictors thromboxane A2 (TXA2), endothelin (ET)-1 and serotonin further contribute to pulmonary hypertension. Protein kinase C (PKC) isozyme alpha (PKCα) is a known modulator of smooth muscle cell contraction. However, the effects of PKCα deficiency on pulmonary vasoconstriction have not yet been investigated. Thus, the role of PKCα in pulmonary vascular responsiveness to the TXA2 analog U46619, ET-1, serotonin and acute hypoxia was investigated in isolated lungs of PKCα-/- mice and corresponding wild-type mice, with or without prior administration of the PKC inhibitor bisindolylmaleimide I or Gö6976. mRNA was quantified from microdissected intrapulmonary arteries. We found that broad-spectrum PKC inhibition reduced pulmonary vascular responsiveness to ET-1 and acute hypoxia and, by trend, to U46619. Analogously, selective inhibition of conventional PKC isozymes or PKCα deficiency reduced ET-1-evoked pulmonary vasoconstriction. The pulmonary vasopressor response to serotonin was unaffected by either broad PKC inhibition or PKCα deficiency. Surprisingly, PKCα-/- mice showed pulmonary vascular hyperresponsiveness to U46619 and increased TXA2 receptor (TP receptor) expression in the intrapulmonary arteries. To conclude, PKCα regulates ET-1-induced pulmonary vasoconstriction. However, PKCα deficiency leads to pulmonary vascular hyperresponsiveness to TXA2, possibly via increased pulmonary arterial TP receptor expression.


Assuntos
Proteína Quinase C-alfa/deficiência , Artéria Pulmonar/efeitos dos fármacos , Receptores de Tromboxano A2 e Prostaglandina H2/agonistas , Tromboxano A2/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Animais , Relação Dose-Resposta a Droga , Endotelina-1/farmacologia , Feminino , Genótipo , Camundongos da Linhagem 129 , Camundongos Knockout , Fenótipo , Proteína Quinase C-alfa/antagonistas & inibidores , Proteína Quinase C-alfa/genética , Inibidores de Proteínas Quinases/farmacologia , Artéria Pulmonar/enzimologia , Receptores de Tromboxano A2 e Prostaglandina H2/genética , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Serotonina/farmacologia , Regulação para Cima
8.
J Infect Dis ; 211(11): 1822-30, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25512625

RESUMO

BACKGROUND: Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide. During pneumococcal pneumonia, the human airway epithelium is exposed to large amounts of H2O2 as a product of host and pathogen oxidative metabolism. Airway cells are known to be highly vulnerable to oxidant damage, but the pathophysiology of oxidative stress induced by S. pneumoniae and the role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant systems of the host are not well characterized. METHODS: For gluthation/gluthathion disulfide analysis BEAS-2B cells, primary broncho-epithelial cells (pBEC), explanted human lung tissue and mouse lungs were infected with different S. pneumoniae strains (D39, A66, R6x, H2O2/pneumolysin/LytA- deficient mutants of R6x). Cell death was proven by LDH assay and cell viability by IL-8 ELISA. The translocation of Nrf2 and the expression of catalase were shown via Western blot. The binding of Nrf2 at the catalase promoter was analyzed by ChIP. RESULTS: We observed a significant induction of oxidative stress induced by S. pneumoniae in vivo, ex vivo, and in vitro. Upon stimulation, the oxidant-responsive transcription factor Nrf2 was activated, and catalase was upregulated via Nrf2. The pneumococci-induced oxidative stress was independent of S. pneumoniae-derived H2O2 and pneumolysin but depended on the pneumococcal autolysin LytA. The Nrf2 inducer resveratrol, as opposed to catalase, reversed oxidative stress in lung epithelial cells. CONCLUSIONS: These observations indicate a H2O2-independent induction of oxidative stress in lung epithelial cells via the release of bacterial factors of S. pneumoniae. Resveratrol might be an option for prevention of acute lung injury and inflammatory responses observed in pneumococcal pneumonia.


Assuntos
Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Pneumonia Pneumocócica/imunologia , Estilbenos/farmacologia , Streptococcus pneumoniae/imunologia , Animais , Antioxidantes/farmacologia , Autólise , Proteínas de Bactérias/metabolismo , Linhagem Celular , Sobrevivência Celular , Células Epiteliais/imunologia , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Interleucina-8/metabolismo , Pulmão/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Pneumocócica/microbiologia , Pneumonia Pneumocócica/fisiopatologia , Resveratrol , Estreptolisinas/metabolismo
9.
Ann Anat ; 196(5): 365-71, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24862691

RESUMO

Megaesophagus in mice has been associated with several genetic defects. In the present study we expand the range of genes associated with esophageal function and morphology by protein kinase C alpha (PKCα). PKCα-deficient mice showed a six times increased prevalence of megaesophagus at the age of 9-10 weeks compared to wild-type animals. In contrast, in a restricted number of 14-month-old animals of both genotypes a similar prevalence of megaesophagus was found. Megaesophagus was associated with an increased portion of the distal esophagus lined by smooth muscle cells. Achalasia-like degeneration or loss of neuronal cells, inflammation or fibrosis was not present in any of the animals. The results of the study therefore suggest that PKCα expression is associated with a delayed replacement of embryonic smooth muscle by skeletal muscle at the distal esophagus and consecutive megaesophagus in young mice, which, however, is not present at the same prevalence at an advanced age.


Assuntos
Acalasia Esofágica/genética , Acalasia Esofágica/patologia , Esôfago/patologia , Miócitos de Músculo Liso/patologia , Proteína Quinase C-alfa/deficiência , Actinas/metabolismo , Animais , Esfíncter Esofágico Inferior/patologia , Esôfago/crescimento & desenvolvimento , Camundongos , Camundongos Knockout
10.
J Immunol ; 188(2): 811-7, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22156592

RESUMO

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. In this study, we examine an innate immune recognition pathway that senses pneumococcal infection, triggers type I IFN production, and regulates RANTES production. We found that human and murine alveolar macrophages as well as murine bone marrow macrophages, but not alveolar epithelial cells, produced type I IFNs upon infection with S. pneumoniae. This response was dependent on the pore-forming toxin pneumolysin and appeared to be mediated by a cytosolic DNA-sensing pathway involving the adapter molecule STING and the transcription factor IFN regulatory factor 3. Indeed, DNA was present in the cytosol during pneumococcal infection as indicated by the activation of the AIM2 inflammasome, which is known to sense microbial DNA. Type I IFNs produced by S. pneumoniae-infected macrophages positively regulated gene expression and RANTES production in macrophages and cocultured alveolar epithelial cells in vitro. Moreover, type I IFNs controlled RANTES production during pneumococcal pneumonia in vivo. In conclusion, we identified an immune sensing pathway detecting S. pneumoniae that triggers a type I IFN response and positively regulates RANTES production.


Assuntos
Quimiocina CCL5/biossíntese , Fator Regulador 3 de Interferon/fisiologia , Interferon Tipo I/biossíntese , Macrófagos Alveolares/imunologia , Proteínas de Membrana/fisiologia , Mucosa Respiratória/imunologia , Streptococcus pneumoniae/imunologia , Animais , Comunicação Autócrina/imunologia , Proteínas de Bactérias/fisiologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Técnicas de Cocultura , Citosol/imunologia , Citosol/metabolismo , DNA Bacteriano/imunologia , DNA Bacteriano/metabolismo , Modelos Animais de Doenças , Humanos , Imunidade Inata , Interferon Tipo I/fisiologia , Pulmão/citologia , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Comunicação Parácrina/imunologia , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Estreptolisinas/fisiologia
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