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1.
PLoS Pathog ; 20(2): e1011840, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38315735

RESUMO

Human metapneumovirus (HMPV) is an important cause of acute lower respiratory infection in children and adults worldwide. There are four genetic subgroups of HMPV and both neutralizing antibodies and T cells contribute to protection. However, little is known about mechanisms of pathogenesis and most published work is based on a few extensively passaged, laboratory-adapted strains of HMPV. In this study, we isolated and characterized a panel of low passage HMPV clinical isolates representing all four genetic subgroups. The clinical isolates exhibited lower levels of in vitro replication compared to a lab-adapted strain. We compared disease phenotypes using a well-established mouse model. Several virulent isolates caused severe weight loss, lung pathology, airway dysfunction, and fatal disease in mice, which was confirmed in three inbred mouse strains. Disease severity did not correlate with lung viral titer, as virulent strains exhibited restricted replication in the lower airway. Virulent HMPV isolates were associated with markedly increased proinflammatory cytokine production and neutrophil influx; however, depletion of neutrophils or genetic ablation of inflammasome components did not reverse disease. Virulent clinical isolates induced markedly increased type I and type III interferon (IFN) secretion in vitro and in vivo. STAT1/2-deficient mice lacking both type I and type III IFN signaling showed reduced disease severity and increased lung viral replication. Inhibition of type I IFN signaling using a blocking antibody or genetic ablation of the type I IFN receptor reduced pathology with minimal effect on viral replication. Conversely, blockade of type III IFN signaling with a neutralizing antibody or genetic ablation of the IFN-lambda receptor had no effect on pathogenesis but restored viral replication. Collectively, these results demonstrate distinct roles for type I and type III IFN in HMPV pathogenesis and immunity.


Assuntos
Metapneumovirus , Infecções por Paramyxoviridae , Infecções Respiratórias , Criança , Animais , Camundongos , Humanos , Interferon lambda , Pulmão , Infecções Respiratórias/patologia , Interferons
2.
J Allergy Clin Immunol ; 153(1): 122-131, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37742934

RESUMO

BACKGROUND: Little is known about nasal epithelial gene expression and total IgE in youth. OBJECTIVE: We aimed to identify genes whose nasal epithelial expression differs by total IgE in youth, and group them into modules that could be mapped to airway epithelial cell types. METHODS: We conducted a transcriptome-wide association study of total IgE in 469 Puerto Ricans aged 9 to 20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study, separately in all subjects and in those with asthma. We then attempted to replicate top findings for each analysis using data from 3 cohorts. Genes with a Benjamini-Hochberg-adjusted P value of less than .05 in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study and a P value of less than .05 in the same direction of association in 1 or more replication cohort were considered differentially expressed genes (DEGs). DEGs for total IgE in subjects with asthma were further dissected into gene modules using coexpression analysis, and such modules were mapped to specific cell types in airway epithelia using public single-cell RNA-sequencing data. RESULTS: A higher number of DEGs for total IgE were identified in subjects with asthma (n = 1179 DEGs) than in all subjects (n = 631 DEGs). In subjects with asthma, DEGs were mapped to 11 gene modules. The top module for positive correlation with total IgE was mapped to myoepithelial and mucus secretory cells in lower airway epithelia and was regulated by IL-4, IL5, IL-13, and IL-33. Within this module, hub genes included CDH26, FETUB, NTRK2, CCBL1, CST1, and CST2. Furthermore, an enrichment analysis showed overrepresentation of genes in signaling pathways for synaptogenesis, IL-13, and ferroptosis, supporting interactions between interleukin- and acetylcholine-induced responses. CONCLUSIONS: Our findings for nasal epithelial gene expression support neuroimmune coregulation of total IgE in youth with asthma.


Assuntos
Asma , Interleucina-13 , Criança , Humanos , Adolescente , Interleucina-13/genética , Nariz , Transcriptoma , Imunoglobulina E
3.
Artigo em Inglês | MEDLINE | ID: mdl-39028582

RESUMO

Elexacaftor/tezacaftor/ivacaftor (ETI) has made a substantial positive impact for people living with CF (pwCF). However, there can be substantial variability in efficacy, and we lack adequate biomarkers to predict individual response. We thus aimed to identify transcriptomic profiles in nasal respiratory epithelium that predict clinical response to ETI treatment. We obtained nasal epithelial samples from pwCF prior to ETI initiation and performed a transcriptome-wide analysis of baseline gene expression to predict changes in FEV1 (∆FEV1), year's best FEV1 (∆ybFEV1), and body mass index (∆BMI). Using the top differentially expressed genes (DEGs), we generated transcriptomic risk scores (TRS) and evaluated their predictive performance. The study included 40 pwCF aged ≥6 years (mean 27.7 [SD=15.1] years; 40% female). After ETI initiation, FEV1 improved ≥5% in 22 (61.1%) participants and ybFEV1 improved ≥5% in 19 (50%). TRS were constructed using top over-expressed and under-expressed genes for each. Adding the ∆FEV1 TRS for to a model with age, sex, and baseline FEV1 increased the AUC from 0.41 to 0.88; the ∆ybFEV1 TRS increased the AUC from 0.51 to 0.88; and the ∆BMI TRS increased the AUC from 0.46 to 0.92. Average accuracy was thus ~85% in predicting the response to the three outcomes. Results were similar in models further adjusted for F508del zygosity and previous CFTR modulator use. In conclusion, we identified nasal epithelial transcriptomic profiles that help accurately predict changes in FEV1 and BMI with ETI treatment. These novel TRS could serve as predictive biomarkers for clinical response to modulator treatment in pwCF.

4.
Am J Physiol Lung Cell Mol Physiol ; 327(2): L189-L202, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38810239

RESUMO

Children are susceptible to influenza infections and can experience severe disease presentation due to a lack of or limited pre-existing immunity. Despite the disproportionate impact influenza has on this population, there is a lack of focus on pediatric influenza research, particularly when it comes to identifying the pathogenesis of long-term outcomes that persist beyond the point of viral clearance. In this study, juvenile outbred male and female mice were infected with influenza and analyzed following viral clearance to determine how sex impacts the persistent inflammatory responses to influenza. It was found that females maintained a broader cytokine response in the lung following clearance of influenza, with innate, type I and type II cytokine signatures in almost all mice. Males, on the other hand, had higher levels of IL-6 and other macrophage-related cytokines, but no evidence of a type I or type II response. The immune landscape was similar in the lungs between males and females postinfection, but males had a higher regulatory T cell to TH1 ratio compared with female mice. Cytokine production positively correlated with the frequency of TH1 cells and exudate macrophages, as well as the number of cells in the bronchoalveolar lavage fluid. Furthermore, female lungs were enriched for metabolites involved in the glycolytic pathway, suggesting glycolysis is higher in female lungs compared with males after viral clearance. These data suggest juvenile female mice have persistent and excessive lung inflammation beyond the point of viral clearance, whereas juvenile males had a more immunosuppressive phenotype.NEW & NOTEWORTHY This study identifies sex-based differences in persistent lung inflammation following influenza infection in an outbred, juvenile animal model of pediatric infection. These findings indicate the importance of considering sex and age as variable in infectious disease research.


Assuntos
Citocinas , Infecções por Orthomyxoviridae , Pneumonia , Caracteres Sexuais , Animais , Feminino , Masculino , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/metabolismo , Camundongos , Citocinas/metabolismo , Pneumonia/virologia , Pneumonia/patologia , Pneumonia/imunologia , Pneumonia/metabolismo , Pulmão/virologia , Pulmão/patologia , Pulmão/imunologia , Pulmão/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Macrófagos/virologia , Fatores Sexuais
5.
J Allergy Clin Immunol ; 152(4): 887-898, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37271320

RESUMO

BACKGROUND: Expression quantitative trait methylation (eQTM) analyses uncover associations between DNA methylation markers and gene expression. Most eQTM analyses of complex diseases have focused on cis-eQTM pairs (within 1 megabase). OBJECTIVES: This study sought to identify cis- and trans-methylation markers associated with gene expression in airway epithelium from youth with and without atopic asthma. METHODS: In this study, the investigators conducted both cis- and trans-eQTM analyses in nasal (airway) epithelial samples from 158 Puerto Rican youth with atopic asthma and 100 control subjects without atopy or asthma. The investigators then attempted to replicate their findings in nasal epithelial samples from 2 studies of children, while also examining whether their results in nasal epithelium overlap with those from an eQTM analysis in white blood cells from the Puerto Rican subjects. RESULTS: This study identified 9,108 cis-eQTM pairs and 2,131,500 trans-eQTM pairs. Trans-associations were significantly enriched for transcription factor and microRNA target genes. Furthermore, significant cytosine-phosphate-guanine sites (CpGs) were differentially methylated in atopic asthma and significant genes were enriched for genes differentially expressed in atopic asthma. In this study, 50.7% to 62.6% of cis- and trans-eQTM pairs identified in Puerto Rican youth were replicated in 2 smaller cohorts at false discovery rate-adjusted P < .1. Replicated genes in the trans-eQTM analysis included biologically plausible asthma-susceptibility genes (eg, HDC, NLRP3, ITGAE, CDH26, and CST1) and are enriched in immune pathways. CONCLUSIONS: Studying both cis- and trans-epigenetic regulation of airway epithelial gene expression can identify potential causal and regulatory pathways or networks for childhood asthma. Trans-eQTM CpGs may regulate gene expression in airway epithelium through effects on transcription factor and microRNA target genes.


Assuntos
Asma , MicroRNAs , Criança , Adolescente , Humanos , Transcriptoma , Epigênese Genética , Asma/metabolismo , Metilação de DNA , Epitélio/metabolismo , Marcadores Genéticos , Mucosa Nasal/metabolismo , Fatores de Transcrição/genética , MicroRNAs/genética , MicroRNAs/metabolismo
6.
Pediatr Allergy Immunol ; 33(4): e13776, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35470932

RESUMO

BACKGROUND: The mechanisms underlying the known link between overweight/obesity and childhood asthma are unclear. We aimed to identify differentially expressed genes and pathways associated with obesity-related asthma through a transcriptomic analysis of nasal airway epithelium. METHODS: We compared the whole transcriptome in nasal airway epithelium of youth with overweight or obesity and asthma with that of youth of normal weight and asthma, using RNA sequencing data from a cohort of 235 Puerto Ricans aged 9-20 years (EVA-PR) and an independent cohort of 66 children aged 6-16 years in Pittsburgh (VDKA). Differential expression analysis adjusting for age, sex, sequencing plate number, and sample sorting protocol, and the first five principal components were performed independently in each cohort. Results from the two cohorts were combined in a transcriptome-wide meta-analysis. Gene enrichment and network analyses were performed on top genes. RESULTS: In the meta-analysis, 29 genes were associated with obesity-related asthma at an FDR-adjusted p <.05, including pro-inflammatory genes known to be differentially expressed in adipose tissue of obese subjects (e.g., CXCL11, CXCL10, and CXCL9) and several novel genes. Functional enrichment analyses showed that pathways for interferon signaling, and innate and adaptive immune responses were down-regulated in overweight/obese youth with asthma, while pathways related to ciliary structure or function were up-regulated. Upstream regulatory analysis predicted significant inhibition of the IRF7 pathway. Network analyses identified "hub" genes like GBP5 and SOCS1. CONCLUSION: Our transcriptome-wide analysis of nasal airway epithelium identified biologically plausible genes and pathways for obesity-related asthma in youth.


Assuntos
Asma , Sobrepeso , Adolescente , Criança , Epitélio/metabolismo , Perfilação da Expressão Gênica , Humanos , Obesidade/genética , Sobrepeso/genética , Transcriptoma
7.
Ann Allergy Asthma Immunol ; 127(2): 236-242.e1, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33892162

RESUMO

BACKGROUND: Age- and sex-related differences in asthma may be due to changes in sex hormone levels. OBJECTIVE: To evaluate whether a change in free testosterone or free testosterone-to-estradiol ratio is associated with changes in lung function and eosinophils in the Puerto Rican youth. METHODS: We tested for the association between the change in sex hormone levels and change in lung function or change in eosinophils in a prospective study of 317 children (with and without asthma) followed up from ages 6 to 14 years to ages 10 to 20 years (146 females, 171 males) in San Juan, Puerto Rico. Serum levels of testosterone, estradiol, sex hormone-binding globulin, and progesterone were measured at 2 study visits, approximately 4.9 years apart. Using testosterone and sex hormone-binding globulin levels, we derived free testosterone and the free testosterone-to-estradiol ratio. Multivariable linear regression was used for the analysis of change in lung function and eosinophils, conducted separately by sex. RESULTS: In girls, each quartile increment in the free testosterone-to-estradiol ratio was associated with a 2.03% increment in percent predicted forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) between study visits. In males, each quartile increment in the free testosterone-to-estradiol ratio was associated with a 3.27% increment in percent predicted FEV1 and a 1.81% increment in percent predicted FEV1/FVC between study visits. In girls with asthma, an increased free testosterone-to-estradiol ratio was significantly associated with decreased eosinophils between visits (P=0.03). CONCLUSION: In Puerto Rican youth, increased free testosterone-to-estradiol ratio over time was associated with an increased FEV1/FVC in both sexes, and with an increased FEV1 in males.


Assuntos
Asma/epidemiologia , Estradiol/sangue , Testes de Função Respiratória , Testosterona/sangue , Adolescente , Asma/imunologia , Asma/patologia , Criança , Eosinófilos/citologia , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Progesterona/sangue , Estudos Prospectivos , Porto Rico/epidemiologia , Globulina de Ligação a Hormônio Sexual/análise , Adulto Jovem
8.
J Cell Sci ; 129(1): 51-64, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26604221

RESUMO

Cardiolipin (also known as PDL6) is an indispensable lipid required for mitochondrial respiration that is generated through de novo synthesis and remodeling. Here, the cardiolipin remodeling enzyme, acyl-CoA:lysocardiolipin-acyltransferase-1 (Alcat1; SwissProt ID, Q6UWP7) is destabilized in epithelia by lipopolysaccharide (LPS) impairing mitochondrial function. Exposure to LPS selectively decreased levels of carbon 20 (C20)-containing cardiolipin molecular species, whereas the content of C18 or C16 species was not significantly altered, consistent with decreased levels of Alcat1. Alcat1 is a labile protein that is lysosomally degraded by the ubiquitin E3 ligase Skp-Cullin-F-box containing the Fbxo28 subunit (SCF-Fbxo28) that targets Alcat1 for monoubiquitylation at residue K183. Interestingly, K183 is also an acetylation-acceptor site, and acetylation conferred stability to the enzyme. Histone deacetylase 2 (HDAC2) interacted with Alcat1, and expression of a plasmid encoding HDAC2 or treatment of cells with LPS deacetylated and destabilized Alcat1, whereas treatment of cells with a pan-HDAC inhibitor increased Alcat1 levels. Alcat1 degradation was partially abrogated in LPS-treated cells that had been silenced for HDAC2 or treated with MLN4924, an inhibitor of Cullin-RING E3 ubiquitin ligases. Thus, LPS increases HDAC2-mediated Alcat1 deacetylation and facilitates SCF-Fbxo28-mediated disposal of Alcat1, thus impairing mitochondrial integrity.


Assuntos
Aciltransferases/metabolismo , Epitélio/metabolismo , Lipopolissacarídeos/farmacologia , Mitocôndrias/enzimologia , Oxigênio/metabolismo , Proteólise/efeitos dos fármacos , Animais , Cardiolipinas/metabolismo , Linhagem Celular , Epitélio/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Histona Desacetilase 2/metabolismo , Lisina/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Camundongos , Modelos Biológicos , Proteínas Ligases SKP Culina F-Box/metabolismo , Ubiquitina/metabolismo , Ubiquitinação/efeitos dos fármacos
9.
J Immunol ; 196(3): 963-77, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26729801

RESUMO

IL-13 and IL-17A, produced mainly by Th2 and Th17 cells, respectively, have an influential role in asthma pathogenesis. We examined the role of IL-13 and IL-17A in mediating airway hyperresponsiveness (AHR), lung inflammation, and mucus metaplasia in a dual Th2/Th17 model of asthma. IL-13 and/or IL-17A were neutralized using mAbs. Th2/Th17 adoptive transfer induced a mixed asthma phenotype characterized by elevated eosinophilia and neutrophilia, tissue inflammation, mucus metaplasia, and AHR that were partially reversible with steroid treatment. Pulmonary inflammation and quasi-static lung compliance were largely unaffected by neutralization of IL-13 and/or IL-17A. However, neutralization of IL-13 alone or in combination with IL-17A significantly attenuated AHR and mucus metaplasia. Further, STAT6 activation was attenuated following IL-13 and IL-13/IL-17A Ab treatment. We next assessed the role of STAT6 in Th2/Th17-mediated allergic airway disease using STAT6(-/-) mice. STAT6(-/-) mice adoptively transferred with Th2/Th17 cells had decreased AHR compared with controls. These data suggest that IL-13 drives AHR and mucus metaplasia in a STAT6-dependent manner, without directly contributing to airway or tissue inflammation. IL-17A independently contributes to AHR, but it only partially mediates inflammation and mucus metaplasia in a mixed Th2/Th17 model of steroid-resistant asthma.


Assuntos
Asma/imunologia , Interleucina-13/imunologia , Interleucina-17/imunologia , Hipersensibilidade Respiratória/imunologia , Transferência Adotiva , Animais , Asma/patologia , Modelos Animais de Doenças , Resistência a Medicamentos , Immunoblotting , Metaplasia/imunologia , Metaplasia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Muco/imunologia , Reação em Cadeia da Polimerase , Hipersensibilidade Respiratória/patologia , Células Th17/imunologia , Células Th2/imunologia , Transcriptoma
10.
Am J Respir Crit Care Med ; 194(7): 807-820, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27007260

RESUMO

RATIONALE: Infection with Pneumocystis, an opportunistic fungal pathogen, can result in fulminant pneumonia in the clinical setting of patients with immunosuppression. In murine models, Pneumocystis has previously been shown to induce a CD4+ T cell-dependent eosinophilic response in the lung capable of providing protection. OBJECTIVES: We sought to explore the role of Pneumocystis in generating asthma-like lung pathology, given the natural eosinophilic response to infection. METHODS: Pneumocystis infection or antigen treatment was used to induce asthma-like pathology in wild-type mice. The roles of CD4+ T cells and eosinophils were examined using antibody depletion and knockout mice, respectively. The presence of anti-Pneumocystis antibodies in human serum samples was detected by ELISA and Western blotting. MEASUREMENTS AND MAIN RESULTS: Pneumocystis infection generates a strong type II response in the lung that requires CD4+ T cells. Pneumocystis infection was capable of priming a Th2 response similar to that of a commonly studied airway allergen, the house dust mite. Pneumocystis antigen treatment was also capable of inducing allergic inflammation in the lung, resulting in anti-Pneumocystis IgE production, goblet cell hyperplasia, and increased airway resistance. In the human population, patients with severe asthma had increased levels of anti-Pneumocystis IgG and IgE compared with healthy control subjects. Patients with severe asthma with elevated anti-Pneumocystis IgG levels had worsened symptom scores and lung parameters such as decreased forced expiratory volume and increased residual volume compared with patients with severe asthma who had low anti-Pneumocystis IgG. CONCLUSIONS: The present study demonstrates for the first time, to our knowledge, that Pneumocystis is an airway allergen capable of inducing asthma-like lung pathology.

11.
J Allergy Clin Immunol ; 136(3): 747-756.e4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25930197

RESUMO

BACKGROUND: Single nucleotide polymorphisms in the human gene for the receptor for advanced glycation end-products (RAGE) are associated with an increased incidence of asthma. RAGE is highly expressed in the lung and has been reported to play a vital role in the pathogenesis of murine models of asthma/allergic airway inflammation (AAI) by promoting expression of the type 2 cytokines IL-5 and IL-13. IL-5 and IL-13 are prominently secreted by group 2 innate lymphoid cells (ILC2s), which are stimulated by the proallergic cytokine IL-33. OBJECTIVE: We sought to test the hypothesis that pulmonary RAGE is necessary for allergen-induced ILC2 accumulation in the lung. METHODS: AAI was induced in wild-type and RAGE knockout mice by using IL-33, house dust mite extract, or Alternaria alternata extract. RAGE's lung-specific role in type 2 responses was explored with bone marrow chimeras and induction of gastrointestinal type 2 immune responses. RESULTS: RAGE was found to drive AAI by promoting IL-33 expression in response to allergen and by coordinating the inflammatory response downstream of IL-33. Absence of RAGE impedes pulmonary accumulation of ILC2s in models of AAI. Bone marrow chimera studies suggest that pulmonary parenchymal, but not hematopoietic, RAGE has a central role in promoting AAI. In contrast to the lung, the absence of RAGE does not affect IL-33-induced ILC2 influx in the spleen, type 2 cytokine production in the peritoneum, or mucus hypersecretion in the gastrointestinal tract. CONCLUSIONS: For the first time, this study demonstrates that a parenchymal factor, RAGE, mediates lung-specific accumulation of ILC2s.


Assuntos
Asma/imunologia , Imunidade Inata , Interleucina-33/imunologia , Pulmão/imunologia , Linfócitos/imunologia , Receptor para Produtos Finais de Glicação Avançada/imunologia , Alérgenos/administração & dosagem , Alérgenos/imunologia , Alternaria/química , Animais , Antígenos de Dermatophagoides/administração & dosagem , Antígenos de Dermatophagoides/imunologia , Asma/induzido quimicamente , Asma/genética , Asma/patologia , Medula Óssea/imunologia , Medula Óssea/patologia , Proliferação de Células , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/patologia , Regulação da Expressão Gênica , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-33/genética , Interleucina-5/genética , Interleucina-5/imunologia , Pulmão/patologia , Linfócitos/patologia , Camundongos , Especificidade de Órgãos , Peritônio/imunologia , Peritônio/patologia , Pyroglyphidae/química , Receptor para Produtos Finais de Glicação Avançada/genética , Transdução de Sinais , Baço/imunologia , Baço/patologia , Quimeras de Transplante
13.
Ann Am Thorac Soc ; 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38986136

RESUMO

BACKGROUND: Little is known about long-term PM2.5 exposure and airway epithelial gene expression. OBJECTIVE: To test for association between long-term PM2.5 exposure and nasal epithelial gene expression in youth with asthma. METHODS: Transcriptome-wide association study (TWAS) of long-term PM2.5 in nasal epithelium from youth aged 6-20 years in the: 1) Epigenetic Variation and Childhood Asthma in Puerto Ricans study (EVA-PR, n=182); 2) Vitamin D Kids Asthma Study (VDKA, n=58); and 3) Stress and Treatment Response in Puerto Rican and African American Children with Asthma study (STAR, n=81). Satellite hybrid models were used to estimate PM2.5 exposure in the prior year at each participant's residence. Multivariable negative binomial regression was used for each TWAS, adjusting for age, sex, and other covariates. A meta-analysis of all TWAS results was then conducted using an inverse variance-weighted average approach. RESULTS: Most participants (~95%) in the meta-analysis of TWAS for PM2.5 exposure identified as Puerto Rican or Black. Long-term PM2.5 was associated with: 1) upregulated expression of CLCA1 (calcium-activated chloride channel regulator 1, false discovery rate-adjusted P [FDR-P]=0.008), SYCP2 (synaptonemal complex protein 2, FDR-P=0.01), and CYP2A6 (cytochrome p450 family 2 subfamily A member 6, FDR-P=0.02), and 2) downregulated expression of EDAR (ectodysplasin A receptor, FDR-P=0.01). In a meta-analysis, CLCA1 upregulation was associated with ≥1 positive allergen-specific IgE (FDR-P <0.001) and increased blood eosinophils (FDR-P <0.001) and total IgE (FDR-P <0.001). CONCLUSIONS: In a meta-analysis of TWASs in predominantly Puerto Rican and Black youth with asthma, long-term PM2.5 exposure was associated with upregulated airway epithelial CLCA1 expression, in turn linked to biomarkers of T2-high immunity.

14.
Mucosal Immunol ; 17(3): 476-490, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38176655

RESUMO

Respiratory viral infections, including human metapneumovirus (HMPV), remain a leading cause of morbidity and mortality in neonates and infants. However, the mechanisms behind the increased sensitivity to those respiratory viral infections in neonates are poorly understood. Neonates, unlike adults, have several anti-inflammatory mechanisms in the lung, including elevated baseline expression of programmed death ligand 1 (PD-L1), a ligand for the inhibitory receptor programmed cell death protein 1 (PD-1). We thus hypothesized that neonates would rely on PD-1:PD-L1 signaling to restrain antiviral CD8 responses. To test this, we developed a neonatal primary HMPV infection model using wild-type C57BL/6 (B6) and Pdcd1-/- (lacking PD-1) mice. HMPV-infected neonatal mice had increased PD-L1/PD-L2 co-expression on innate immune cells but a similar number of antigen-specific CD8+ T cells and upregulation of PD-1 to that of adult B6 mice. Neonatal CD8+ T cells had reduced interferon-gamma (IFN-γ), granzyme B, and interleukin-2 production compared with B6 adults. Pdcd1-/- neonatal CD8+ T cells had markedly increased production of IFN-γ and granzyme B compared with B6 neonates. Pdcd1-/- neonates had increased acute pathology with HMPV or influenza. Pdcd1-/- neonates infected with HMPV had long-term changes in pulmonary physiology with evidence of immunopathology and a persistent CD8+ T-cell response with increased granzyme B production. Using single-cell ribonucleic acid sequencing from a child lacking PD-1 signaling, a similar activated CD8+ T-cell signature with increased granzyme B expression was observed. These data indicate that PD-1 signaling critically limits CD8+ T-cell effector functions and prevents immunopathology in response to neonatal respiratory viral infections.


Assuntos
Animais Recém-Nascidos , Linfócitos T CD8-Positivos , Metapneumovirus , Camundongos Knockout , Infecções por Paramyxoviridae , Receptor de Morte Celular Programada 1 , Transdução de Sinais , Animais , Linfócitos T CD8-Positivos/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/genética , Camundongos , Humanos , Metapneumovirus/imunologia , Infecções por Paramyxoviridae/imunologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Camundongos Endogâmicos C57BL , Granzimas/metabolismo , Granzimas/genética , Modelos Animais de Doenças , Infecções Respiratórias/imunologia , Infecções Respiratórias/virologia
15.
RNA ; 17(1): 108-19, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21088109

RESUMO

Thirty-one RNA duplexes containing single-nucleotide bulge loops were optically melted in 1 M NaCl, and the thermodynamic parameters ΔH°, ΔS°, ΔG°(37), and T(M) for each sequence were determined. The bulge loops were of the group II variety, where the bulged nucleotide is identical to one of its nearest neighbors, leading to ambiguity as to the exact position of the bulge. The data were used to develop a model to predict the free energy of an RNA duplex containing a single-nucleotide bulge. The destabilization of the duplex by the bulge was primarily related to the stability of the stems adjacent to the bulge. Specifically, there was a direct correlation between the destabilization of the duplex and the stability of the less stable duplex stem. Since there is an ambiguity of the bulge position for group II bulges, several different stem combinations are possible. The destabilization of group II bulge loops is similar to the destabilization of group I bulge loops, if the second least stable stem is used to predict the influence of the group II bulge. In-line structure probing of the group II bulge loop embedded in a hairpin indicates that the bulged nucleotide is the one positioned farther from the hairpin loop.


Assuntos
Estabilidade de RNA , RNA/química , Modelos Moleculares , Conformação de Ácido Nucleico , RNA/genética , Termodinâmica
16.
Curr Allergy Asthma Rep ; 13(6): 587-95, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23760974

RESUMO

The TH17 lineage of T cells and its canonical cytokine IL-17 have been the focus of many recent studies in autoimmune, allergic, and infectious disease. In this review, we will briefly discuss the current knowledge about the role of these cells and IL-17 in a spectrum of disorders. It is clear that IL-17 plays pathogenic roles in certain conditions while the same pathway is critically important to immunity in others. Targeting of TH17 cells or IL-17 therapeutically may impart many benefits, but this approach is not without potentially serious implications regarding host defense. These issues will be discussed herein as we evaluate pharmacological approaches targeting this pathway that are just beginning to be fully tested in human disease.


Assuntos
Asma/imunologia , Doenças Autoimunes/imunologia , Hipersensibilidade/imunologia , Interleucina-17/imunologia , Células Th17/imunologia , Humanos , Interleucina-23/imunologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-37293566

RESUMO

Obesity and associated changes to the gut microbiome worsen airway inflammation and hyperresponsiveness in asthma. Obesogenic host-microbial metabolomes have altered production of metabolites that may influence lung function and inflammatory responses in asthma. To understand the interplay of the gut microbiome, metabolism, and host inflammation in obesity-associated asthma, we used a multi-omics approach to profile the gut-lung axis in the setting of allergic airway disease and diet-induced obesity. We evaluated an immunomodulator, nitro-oleic acid (NO2-OA), as a host- and microbial-targeted treatment intervention for obesity-associated allergic asthma. Allergic airway disease was induced using house dust mite and cholera toxin adjuvant in C57BL6/J mice with diet-induced obesity to model obesity-associated asthma. Lung function was measured by flexiVent following a week of NO2-OA treatment and allergen challenge. 16S rRNA gene (from DNA, taxa presence) and 16S rRNA (from RNA, taxa activity) sequencing, metabolomics, and host gene expression were paired with a Treatment-Measured-Response model as a data integration framework for identifying latent/hidden relationships with linear regression among variables identified from high-dimensional meta-omics datasets. Targeting both the host and gut microbiota, NO2-OA attenuated airway inflammation, improved lung elastance, and modified the gut microbiome. Meta-omics data integration and modeling determined that gut-associated inflammation, metabolites, and functionally active gut microbiota were linked to lung function outcomes. Using Treatment-Measured-Response modeling and meta-omics profiling of the gut-lung axis, we uncovered a previously hidden network of interactions between gut levels of amino acid metabolites involved in elastin and collagen synthesis, gut microbiota, NO2-OA, and lung elastance. Further targeted metabolomics analyses revealed that obese mice with allergic airway disease had higher levels of proline and hydroxyproline in the lungs. NO2-OA treatment reduced proline biosynthesis by downregulation of pyrroline-5-carboxylate reductase 1 (PYCR1) expression. These findings are relevant to human disease: adults with mild-moderate asthma and BMI ≥ 25 had higher plasma hydroxyproline levels. Our results suggest that changes to structural proteins in the lung airways and parenchyma may contribute to heightened lung elastance and serve as a potential therapeutic target for obese allergic asthma.

18.
Am J Physiol Lung Cell Mol Physiol ; 302(1): L160-6, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22003088

RESUMO

The antioxidant enzyme extracellular superoxide dismutase (EC-SOD) is abundant in the lung and is known to limit inflammation and fibrosis following numerous pulmonary insults. Previous studies have reported a loss of full-length EC-SOD from the pulmonary parenchyma with accumulation of proteolyzed EC-SOD in the airspace after an interstitial lung injury. However, following airspace only inflammation, EC-SOD accumulates in the airspace without a loss from the interstitium, suggesting this antioxidant may be released from an extrapulmonary source. Because leukocytes are known to express EC-SOD and are prevalent in the bronchoalveolar lavage fluid (BALF) after injury, it was hypothesized that these cells may transport and release EC-SOD into airspaces. To test this hypothesis, C57BL/6 wild-type and EC-SOD knockout mice were irradiated and transplanted with bone marrow from either wild-type mice or EC-SOD knockout mice. Bone marrow chimeric mice were then intratracheally treated with asbestos and killed 3 and 7 days later. At both 3 and 7 days following asbestos injury, mice without pulmonary EC-SOD expression but with EC-SOD in infiltrating and resident leukocytes did not have detectable levels of EC-SOD in the airspaces. In addition, leukocyte-derived EC-SOD did not significantly lessen inflammation or early stage fibrosis that resulted from asbestos injury in the lungs. Although it is not influential in the asbestos-induced interstitial lung injury model, EC-SOD is still known to be present in leukocytes and may play an influential role in attenuating pneumonias and other inflammatory diseases.


Assuntos
Amianto/administração & dosagem , Leucócitos/enzimologia , Lesão Pulmonar/enzimologia , Pulmão/enzimologia , Superóxido Dismutase/metabolismo , Animais , Amianto/efeitos adversos , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Espaço Extracelular/enzimologia , Sequestradores de Radicais Livres/metabolismo , Inflamação/enzimologia , Pulmão/patologia , Lesão Pulmonar/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/enzimologia , Fibrose Pulmonar/fisiopatologia
19.
Am J Pathol ; 178(6): 2752-9, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21641397

RESUMO

Extracellular superoxide dismutase (EC-SOD) is abundant in the lung and limits inflammation and injury in response to many pulmonary insults. To test the hypothesis that EC-SOD has an important role in bacterial infections, wild-type and EC-SOD knockout (KO) mice were infected with Escherichia coli to induce pneumonia. Although mice in the EC-SOD KO group demonstrated greater pulmonary inflammation than did wild-type mice, there was less clearance of bacteria from their lungs after infection. Macrophages and neutrophils express EC-SOD; however, its function and subcellular localization in these inflammatory cells is unclear. In the present study, immunogold electron microscopy revealed EC-SOD in membrane-bound vesicles of phagocytes. These findings suggest that inflammatory cell EC-SOD may have a role in antibacterial defense. To test this hypothesis, phagocytes from wild-type and EC-SOD KO mice were evaluated. Although macrophages lacking EC-SOD produced more reactive oxygen species than did cells expressing EC-SOD after stimulation, they demonstrated significantly impaired phagocytosis and killing of bacteria. Overall, this suggests that EC-SOD facilitates clearance of bacteria and limits inflammation in response to infection by promoting bacterial phagocytosis.


Assuntos
Escherichia coli/citologia , Espaço Extracelular/enzimologia , Macrófagos/citologia , Macrófagos/enzimologia , Viabilidade Microbiana , Fagocitose , Superóxido Dismutase/metabolismo , Animais , Humanos , Inflamação/microbiologia , Inflamação/patologia , Espaço Intracelular/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxidantes/metabolismo , Pneumonia/microbiologia , Pneumonia/patologia , Superóxido Dismutase/ultraestrutura
20.
Sci Rep ; 11(1): 17788, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493738

RESUMO

Bile acid profiles are altered in obese individuals with asthma. Thus, we sought to better understand how obesity-related systemic changes contribute to lung pathophysiology. We also test the therapeutic potential of nitro-oleic acid (NO2-OA), a regulator of metabolic and inflammatory signaling pathways, to mitigate allergen and obesity-induced lung function decline in a murine model of asthma. Bile acids were measured in the plasma of healthy subjects and individuals with asthma and serum and lung tissue of mice with and without allergic airway disease (AAD). Lung function, indices of inflammation and hepatic bile acid enzyme expression were measured in obese mice with house dust mite-induced AAD treated with vehicle or NO2-OA. Serum levels of glycocholic acid and glycoursodeoxycholic acid clinically correlate with body mass index and airway hyperreactivity whereas murine levels of ß-muricholic acid and tauro-ß-muricholic acid were significantly increased and positively correlated with impaired lung function in obese mice with AAD. NO2-OA reduced murine bile acid levels by modulating hepatic expression of bile acid synthesis enzymes, with a concomitant reduction in small airway resistance and tissue elastance. Bile acids correlate to body mass index and lung function decline and the signaling actions of nitroalkenes can limit AAD by modulating bile acid metabolism, revealing a potential pharmacologic approach to improving the current standard of care.


Assuntos
Asma/metabolismo , Asma/fisiopatologia , Ácidos e Sais Biliares/metabolismo , Ácidos Graxos/fisiologia , Pulmão/fisiopatologia , Nitrocompostos/uso terapêutico , Obesidade/metabolismo , Ácidos Oleicos/uso terapêutico , Adolescente , Adulto , Animais , Antiasmáticos/uso terapêutico , Antígenos de Dermatophagoides/toxicidade , Asma/tratamento farmacológico , Asma/etiologia , Dieta Hiperlipídica/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Ácidos Graxos/química , Feminino , Volume Expiratório Forçado , Ácido Glicocólico/sangue , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/fisiopatologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/metabolismo , Magreza , Ácido Ursodesoxicólico/análogos & derivados , Ácido Ursodesoxicólico/sangue , Capacidade Vital , Adulto Jovem
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