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1.
Front Immunol ; 12: 680334, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421895

RESUMO

Background: Inborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans. Objective: We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency. Methods: We assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells. Results: SOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients. Conclusions: SOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients.


Assuntos
Haploinsuficiência , Sistema Imunitário/metabolismo , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Alelos , Autoimunidade , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Citocinas , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/metabolismo , Humanos , Síndrome de Job/diagnóstico , Síndrome de Job/etiologia , Síndrome de Job/metabolismo , Masculino , Modelos Biológicos , Linhagem , Linfócitos T/imunologia , Linfócitos T/metabolismo
2.
Front Immunol ; 12: 698193, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34381451

RESUMO

HLA molecules are key restrictive elements to present intracellular antigens at the crossroads of an effective T-cell response against SARS-CoV-2. To determine the impact of the HLA genotype on the severity of SARS-CoV-2 courses, we investigated data from 6,919 infected individuals. HLA-A, -B, and -DRB1 allotypes grouped into HLA supertypes by functional or predicted structural similarities of the peptide-binding grooves did not predict COVID-19 severity. Further, we did not observe a heterozygote advantage or a benefit from HLA diplotypes with more divergent physicochemical peptide-binding properties. Finally, numbers of in silico predicted viral T-cell epitopes did not correlate with the severity of SARS-CoV-2 infections. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. Moreover, our data suggest that the spike glycoprotein alone may allow for abundant T-cell epitopes to mount robust T-cell responses not limited by the HLA genotype.


Assuntos
Infecções por Coronavirus/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Adulto , Simulação por Computador , Estudos Transversais , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Genótipo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologia
3.
J Pediatr ; 237: 136-142, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34324882

RESUMO

OBJECTIVE: To evaluate the role of childcare facilities in the transmission of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in a longitudinal study to gain further knowledge of SARS-CoV-2 prevalence, transmission, and spread among preschool children, their parents, and their caregivers. STUDY DESIGN: Children aged 1-6 years, their parents, and their caregivers in 14 childcare facilities in Dresden, Saxony/Germany were invited to participate in the KiTaCoviDD19-study between July 2020 and January 2021. Seroprevalence of SARS-CoV-2 antibodies was assessed up to 4 times during the study period in all participating adults, and demographic characteristics, as well as epidemiologic information on personal SARS-CoV-2 history were obtained. Samples for stool virus shedding of SARS-CoV-2 were analyzed by polymerase chain reaction every 2-4 weeks in all participating children. RESULTS: In total, 318 children, 299 parents and 233 childcare workers were enrolled. By January 2021, 11% of the participating adults were found to be seropositive, whereas the percentage of children shedding SARS-CoV-2 was 6.8%. Overall, we detected 17 children with SARS-CoV-2 virus shedding in 8 different childcare facilities. In 4 facilities, there were a maximum of 3 connected cases in children. Approximately 50% of SARS-CoV-2 infections in the children could not be connected to a secondary case in our study population. CONCLUSIONS: This study does not provide evidence of relevant asymptomatic ("silent") spread of SARS-CoV-2 in childcare facilities in both low- and high-prevalence settings. Our findings add to the evidence that childcare and educational settings do not have a crucial role in driving the SARS-CoV-2 pandemic.


Assuntos
COVID-19/transmissão , Creches/estatística & dados numéricos , Adulto , COVID-19/epidemiologia , Teste para COVID-19/métodos , Criança , Pré-Escolar , Fezes/virologia , Feminino , Alemanha/epidemiologia , Humanos , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pandemias , Pais , Prevalência , Quarentena , Estudos Retrospectivos , SARS-CoV-2 , Eliminação de Partículas Virais
4.
Antibiotics (Basel) ; 10(6)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208657

RESUMO

Carbapenem-resistant Enterobacterales are a growing problem in healthcare systems worldwide. While whole-genome sequencing (WGS) has become a powerful tool for analyzing transmission and possible outbreaks, it remains laborious, and the limitations in diagnostic workflows are not well studied. The aim of this study was to compare the performance of WGS and real-time multiplex PCR (RT-qPCR) for diagnosing carbapenem-resistant Enterobacterales. In this study, we analyzed 92 phenotypically carbapenem-resistant Enterobacterales, sent to the University Hospital Heidelberg in 2019, by the carbapenem inactivation method (CIM) and compared WGS and RT-qPCR as genotypic carbapenemase detection methods. In total, 80.4% of the collected isolates were identified as carbapenemase producers. For six isolates, discordant results were recorded for WGS, PCR and CIM, as the carbapenemase genes were initially not detected by WGS. A reanalysis using raw reads, rather than assembly, highlighted a coverage issue with failure to detect carbapenemases located in contigs with a coverage lower than 10×, which were then discarded. Our study shows that multiplex RT-qPCR and CIM can be a simple alternative to WGS for basic surveillance of carbapenemase-producing Enterobacterales. Using WGS in clinical workflow has some limitations, especially regarding coverage and sensitivity. We demonstrate that antimicrobial resistance gene detection should be performed on the raw reads or non-curated draft genome to increase sensitivity.

5.
Microorganisms ; 9(6)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207425

RESUMO

Little is known about the interplay and contribution of oral microorganisms to allergic diseases, especially in children. The aim of the clinical study was to associate saliva and dental biofilm microbiome with allergic disease, in particular with allergic asthma. In a single-center study, allergic/asthmatic children (n = 15; AA-Chd; age 10.7 ± 2.9), atopic/allergic children (n = 16; AT/AL-Chd; 11.3 ± 2.9), and healthy controls (n = 15; CON-Chd; age 9.9 ± 2.2) were recruited. After removing adhering biofilms from teeth and collecting saliva, microbiome was analyzed by using a 16s-rRNA gene-based next-generation sequencing in these two mediums. Microbiome structure differed significantly between saliva and dental biofilms (ß-diversity). Within the groups, the dental biofilm microbiome of AA-Chd and AT/AL-Chd showed a similar microbial fingerprint characterized by only a small number of taxa that were enriched or depleted (4) compared to the CON-Chd, while both diseased groups showed a stronger microbial shift compared to CON-Chd, revealing 14 taxa in AA-Chd and 15 taxa in AT/AL-Chd that were different. This could be the first note to the contribution of dental biofilm and its metabolic activity to allergic health or disease.

6.
Sci Rep ; 11(1): 14893, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290329

RESUMO

Comparing seroprevalence and antibody kinetics in three different commercially available assays for SARS-CoV-2. Serostatus of COVID-19 patients was analyzed 5 months and 10 months after their infection, using three different assays: Diasorin LIAISON, Euroimmun, Abbott Diagnostics ARCHITECT. Seropositivity at baseline differed significantly depending on the assay (Diasorin 81%, Euroimmun 83%, Abbott 59%). At follow-up antibody levels detected in the Diasorin assay were stable, while there was a significant loss in seropositivity in the Euroimmun and Abbott assays. There are significant differences in SARS-CoV-2 antibody kinetics based on the specific assay used.


Assuntos
Anticorpos Antivirais/análise , Teste para COVID-19/métodos , COVID-19/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/imunologia , COVID-19/epidemiologia , COVID-19/virologia , Criança , Pré-Escolar , Feminino , Alemanha/epidemiologia , Humanos , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Estudos Soroepidemiológicos
7.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200296

RESUMO

Recent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of Nedd4-2 in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na+ channel (ENaC), TGFß signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of Nedd4-2 on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of Nedd4-2 in the lung epithelial cells of neonatal doxycycline-induced triple transgenic Nedd4-2fl/fl/CCSP-rtTA2S-M2/LC1 mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP-C trafficking. We found that the congenital deletion of Nedd4-2 caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of Nedd4-2 in lung epithelial cells caused increased expression of Muc5b and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of Nedd4-2 may support studies of the pathogenesis and preclinical development of therapies for chILD.


Assuntos
Células Epiteliais/patologia , Pulmão/patologia , Ubiquitina-Proteína Ligases Nedd4/fisiologia , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/patologia , Animais , Animais Recém-Nascidos , Células Epiteliais/metabolismo , Feminino , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Alvéolos Pulmonares/imunologia , Alvéolos Pulmonares/metabolismo , Fibrose Pulmonar/etiologia
8.
Epidemiol Infect ; 149: e177, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34325753

RESUMO

In Germany, Eastern regions had a mild first wave of coronavirus disease 2019 (COVID-19) from March to May 2020, but were badly hit by a second wave later in autumn and winter. It is unknown how the second wave was initiated and developed in Eastern Germany where the number of COVID-19 cases was close to zero in June and July 2020. We used genomic epidemiology to investigate the dynamic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage development across the first and second waves in Eastern Germany. With detailed phylogenetic analyses we could show that SARS-CoV-2 lineages prevalent in the first and second waves in Eastern Germany were different, with several new variants including four predominant lineages in the second wave, having been introduced into Eastern Germany between August and October 2020. The results indicate that the major driving force behind the second wave was the introduction of new variants.


Assuntos
COVID-19/epidemiologia , Genoma Viral , Pandemias , SARS-CoV-2/genética , COVID-19/virologia , Alemanha/epidemiologia , Humanos , Filogenia , SARS-CoV-2/classificação
9.
BMJ Paediatr Open ; 5(1): e001036, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34192197

RESUMO

Objective: To quantify the number of undetected SARS-CoV-2 infections in educational settings. Design: Serial SARS-CoV-2 seroprevalence study before and during the second wave of the COVID-19 pandemic. Setting: Secondary school in Dresden, Germany. Participants: Grade 8-12 students and their teachers were invited to participate in serial blood sampling and SARS-CoV-2 IgG antibody assessment. Main outcome measure: Seroprevalence of SARS-CoV-2 antibodies in study population. Results: 247 students and 55 teachers participated in the initial study visit and 197 students and 40 teachers completed follow-up. Seroprevalence increased from 1.7% (0.3-3.3) to 6.8% (3.8-10.1) during the study period mirroring the increase of officially reported SARS-CoV-2 infections during this time. The ratio of undetected to detected SARS-CoV-2 infections ranged from 0.25 to 0.33. Conclusions: We could not find evidence of relevant silent, asymptomatic spread of SARS-CoV-2 in schools neither in a low prevalence setting nor during the second wave of the pandemic, making it unlikely that educational settings play a crucial role in driving the SARS-CoV-2 pandemic. Trial registration number: DRKS00022455.

11.
BMJ Open ; 11(6): e049876, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112645

RESUMO

OBJECTIVE: To quantify the number of SARS-CoV-2 infections in secondary schools after their reopening in May 2020. DESIGN: Repeated SARS-CoV-2 seroprevalence study after the reopening of schools and 4 months later. SETTING: Secondary school in Dresden, Germany. PARTICIPANTS: 1538 students grades 8-12 and 507 teachers from 13 schools. INTERVENTIONS: Serial blood sampling and SARS-CoV-2 IgG antibody assessment. PRIMARY AND SECONDARY OUTCOME MEASURE: Seroprevalence of SARS-CoV-2 antibodies in study population. Number of undetected cases. RESULTS: 1538 students and 507 teachers were initially enrolled, and 1334 students and 445 teachers completed both study visits. The seroprevalence for SARS-CoV-2 antibodies was 0.6% in May/June and the same in September/October. Even in schools with reported COVID-19 cases before the lockdown of 13 March, no clusters could be identified. Of 12 persons with positive serology five had a known history of confirmed COVID-19; 23 out of 24 participants with a household history of COVID-91 were seronegative. CONCLUSIONS: Schools do not play a crucial role in driving the SARS-CoV-2 pandemic in a low-prevalence setting. Transmission in families occurs very infrequently, and the number of unreported cases is low in this age group. These observations do not support school closures as a strategy fighting the pandemic in a low-prevalence setting. TRIAL REGISTRATION NUMBER: DRKS00022455.


Assuntos
COVID-19 , SARS-CoV-2 , Controle de Doenças Transmissíveis , Alemanha/epidemiologia , Humanos , Estudos Longitudinais , Instituições Acadêmicas , Estudos Soroepidemiológicos , Estudantes
12.
J Invest Dermatol ; 141(11): 2611-2619.e2, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33894197

RESUMO

Loss of FLG causes ichthyosis vulgaris. Reduced FLG expression compromises epidermal barrier function and is associated with atopic dermatitis, allergy, and asthma. The flaky tail mouse harbors two mutations that affect the skin barrier, Flgft, resulting in hypomorphic FLG expression, and Tmem79ma, inactivating TMEM79. Mice defective only for TMEM79 featured dermatitis and systemic atopy, but also Flgft/ft BALB/c congenic mice developed eczema, high IgE, and spontaneous asthma, suggesting that FLG protects from atopy. In contrast, a targeted Flg-knockout mutation backcrossed to BALB/c did not result in dermatitis or atopy. To resolve this discrepancy, we generated FLG-deficient mice on pure BALB/c background by inactivating Flg in BALB/c embryos. These mice feature an ichthyosis phenotype, barrier defect, and facilitated percutaneous sensitization. However, they do not develop dermatitis or atopy. Whole-genome sequencing of the atopic Flgft BALB/c congenics revealed that they were homozygous for the atopy-causing Tmem79matted mutation. In summary, we show that FLG deficiency does not cause atopy in mice, in line with lack of atopic disease in a fraction of patients with ichthyosis vulgaris carrying two Flg null alleles. However, the absence of FLG likely promotes and modulates dermatitis caused by other genetic barrier defects.

14.
J Microbiol Methods ; 185: 106224, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33872637

RESUMO

Fast detection of carbapenemases in Gram-negative bacilli is necessary for accurate antibiotic treatment, prevention of further spreading and surveillance purposes. We analyzed the current occurrence of gene variants and designed two multiplex PCRs with hydrolysis probes. The assay was developed for the BD MAX™ system that combines DNA extraction and PCR in a fully automated procedure providing results within 3 h and was evaluated for detection of carbapenemases from bacterial isolates and directly from rectal swabs. The assay has a theoretic coverage of 97.1% for carbapenemases detected during the last years by the German National Reference Laboratory (NRL). A collection of 151 isolates from the NRL was used and all carbapenemase-positive bacteria (58/58) were identified correctly. The direct-PCR on rectal swabs revealed additional carbapenemase genes in 7 samples that were not identified by the culture-based method used as reference method. The assay allows detection of carbapenemases from clinical isolates and might also help in rapid detection directly from rectal samples.

15.
Diagn Microbiol Infect Dis ; 100(4): 115382, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33930691

RESUMO

Sensitivity and specificity of serological assays are key parameters for the accurate estimation of SARS-CoV-2 sero-prevalence. The aim of this study was to compare 8 readily available IgG antibody tests using a panel of well-defined serum samples of prepandemic and pandemic origin. A cross-reaction panel included samples of patients with recent infection with either of the endemic Coronaviruses 229E, NL63, HKU1, or OC43. Additionally, samples with high antibody levels against influenza virus, adenovirus, and during acute EBV infection were included. Previous infection with endemic coronaviruses caused a significant amount of cross-reactivity in two of the assays. In contrast, the confidence intervals for the assays of Abbott, DiaSorin, Euroimmun and Roche encompassed the value of 98% for samples with a previous endemic HCoV infection. For all assays, sensitivities were between 91.3% and 98.8%. Assay performance was independent of the usage of either nucleocapsid or spike proteins.


Assuntos
Anticorpos Antivirais/sangue , Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , Imunoglobulina G/sangue , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/imunologia , Teste Sorológico para COVID-19/normas , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Estudos Soroepidemiológicos , Proteínas Virais , Adulto Jovem
16.
Front Cell Infect Microbiol ; 11: 548613, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816324

RESUMO

The development of CFTR modulator therapies significantly changed the treatment scheme of people with cystic fibrosis. However, CFTR modulator therapy is still a life-long treatment, which is not able to correct the genetic defect and cure the disease. Therefore, it becomes crucial to understand the effects of such modulation of CFTR function on the airway physiology, especially on airway infections and inflammation that are currently the major life-limiting factors in people with cystic fibrosis. In this context, understanding the dynamics of airway microbiome changes in response to modulator therapy plays an essential role in developing strategies for managing airway infections. Whether and how the newly available therapies affect the airway microbiome is still at the beginning of being deciphered. We present here a brief review summarizing the latest information about microbiome alterations in light of modern cystic fibrosis modulator therapy.


Assuntos
Fibrose Cística , Microbiota , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Inflamação , Sistema Respiratório
17.
Pathogens ; 10(2)2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673032

RESUMO

Use of wastewater-based epidemiology as a tool to record and manage the course of SARS-CoV-2 infections in human populations requires information about the efficiency of methods to concentrate the virus from wastewater. In the present study, we spiked untreated wastewater with quantified SARS-CoV-2 positive clinical material and enriched the virus by polyethylene glycol precipitation and ultrafiltration with Vivaspin 10 kDa MWCO columns. SARS-CoV-2 was detected and quantified by reverse transcription quantitative PCR (E- and S-gene) and droplet digital PCR. The concentration of virus with precipitation resulted in mean recoveries between 59.4% and 63.7% whereas rates from 33.0% to 42.6% after ultrafiltration of samples were demonstrated. The results suggest that the use of both methods allows an effective and practicable enrichment of SARS-CoV-2 from raw wastewater.

18.
Ann Am Thorac Soc ; 18(6): 971-980, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33600745

RESUMO

Rationale: Previous studies showed that lumacaftor-ivacaftor therapy results in partial rescue of CFTR (cystic fibrosis [CF] transmembrane conductance regulator) activity and a moderate improvement of spirometry in Phe508del homozygous patients with CF. However, the effects of lumacaftor-ivacaftor on lung clearance index (LCI), lung morphology and perfusion detected by chest magnetic resonance imaging (MRI), and effects on the airway microbiome and inflammation remain unknown. Objectives: To investigate the effects of lumacaftor-ivacaftor on LCI, lung MRI scores, and airway microbiome and inflammation. Methods: In this prospective observational study we assessed clinical outcomes including spirometry and body mass index, LCI, lung MRI scores, sputum microbiome, and proinflammatory cytokines in 30 Phe508del homozygous patients with CF 12 years and older before and 8-16 weeks after initiation of lumacaftor-ivacaftor therapy. Results: Lumacaftor-ivacaftor had no effects on forced expiratory volume in 1 second (FEV1% predicted) (1.7%; 95% confidence interval [CI], -1.0% to 4.3%; P = 0.211) but improved LCI (-1.6; 95% CI, -2.6 to -0.5; P < 0.01) and MRI morphology (-1.3; 95% CI, -2.3 to -0.3; P < 0.05) and perfusion score (-1.2; 95% CI, -2.3 to -0.2; P < 0.05) in our study cohort. Furthermore, lumacaftor-ivacaftor decreased the total bacterial load (-1.8; 95% CI, -3.3 to -0.34; P < 0.05) and increased the Shannon diversity of the airway microbiome (0.4; 95% CI, 0.1 to 0.8; P < 0.05), and reduced IL-1ß (interleukin-1ß) concentration (median change, -324.2 pg/ml; 95% CI, -938.7 to 290.4 pg/ml; P < 0.05) in sputum of Phe508del homozygous patients. Conclusions: This study shows that lumacaftor-ivacaftor has beneficial effects on lung ventilation, morphology, and perfusion, as well as on the airway microbiome and inflammation in Phe508del homozygous patients. Our results suggest that LCI and MRI may be more sensitive than FEV1% predicted to detect response to CFTR modulator therapy in patients with chronic CF lung disease. Clinical trial registered with ClinicalTrials.gov (NCT02807415).


Assuntos
Fibrose Cística , Microbiota , Aminofenóis/uso terapêutico , Aminopiridinas , Benzodioxóis , Fibrose Cística/diagnóstico por imagem , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Pulmão/diagnóstico por imagem , Imageamento por Ressonância Magnética , Mutação , Estudos Prospectivos , Quinolonas
19.
J Cyst Fibros ; 20(5): 754-760, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33431308

RESUMO

Airway dysbiosis has been associated with lung disease severity in patients with cystic fibrosis (CF). However, the relationship between dysbiosis, airway inflammation and lung function impairement remains poorly understood. The aim of this study was therefore to determine how the structure of the sputum microbiota, airway inflammation markers and spirometry are related in patients with CF. Sputum samples were collected from 106 CF patients between 12 and 72 years. These were analyzed by 16S rRNA gene amplicon sequencing. Moreover, levels of pro-inflammatory cytokines (IL-1ß, IL-8, IL-6 and TNF-α) and Neutrophil elastase (NE) were determined. The relationship between the microbiota, inflammation markers and forced expiratory volume in one second percent predicted (FEV1% predicted) was evaluated by multi-parameter analysis. The microbiota α-diversity correlated inverse with inflammation markers IL-1ß, IL-8, TNF-α, NE and positively with FEV1% predicted. Patients could be divided into 7 clusters based on their microbiota structure. The most diverse cluster was defined by oropharyngeal-like flora (OF) while the others were characterized by the dominance of a single pathogen. Patients with the diverse OF microbiota cluster had lower sputum inflammatory markers and higher FEV1% predicted compared to patients with a pathogen-dominated microbiota including Pseudomonas aeruginosa. Our results suggest that the diversity of the airway microbiota is an important biomarker of the severity of airway inflammation linking dysbiosis to lung function decline in patients with CF.

20.
J Immunol ; 206(1): 164-180, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33239420

RESUMO

Signal peptide peptidase-like 2a (SPPL2a) is an aspartyl intramembrane protease essential for degradation of the invariant chain CD74. In humans, absence of SPPL2a leads to Mendelian susceptibility to mycobacterial disease, which is attributed to a loss of the dendritic cell (DC) subset conventional DC2. In this study, we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a-/- mice and demonstrate dependence on CD74 using SPPL2a-/- CD74-/- mice. Upon contact with mycobacteria, SPPL2a-/- bone marrow-derived DCs show enhanced secretion of IL-1ß, whereas production of IL-10 and IFN-ß is reduced. These effects correlated with modulated responses upon selective stimulation of the pattern recognition receptors TLR4 and Dectin-1. In SPPL2a-/- bone marrow-derived DCs, Dectin-1 is redistributed to endosomal compartments. Thus, SPPL2a deficiency alters pattern recognition receptor pathways in a CD74-dependent way, shifting the balance from anti- to proinflammatory cytokines in antimycobacterial responses. We propose that in addition to the DC reduction, this altered DC functionality contributes to Mendelian susceptibility to mycobacterial disease upon SPPL2a deficiency.


Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Membrana Celular/metabolismo , Células Dendríticas/imunologia , Proteínas de Membrana/metabolismo , Mycobacterium bovis/fisiologia , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Ácido Aspártico Endopeptidases/genética , Bovinos , Células Cultivadas , Citocinas/metabolismo , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Imunidade , Imunomodulação , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 4 Toll-Like/imunologia , Tuberculose Bovina
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