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1.
Am J Respir Crit Care Med ; 208(10): 1101-1114, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37677136

RESUMEN

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare costs. Cigarette smoke is a causative factor; however, not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advanced stages. Objectives: We investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. Methods: We recruited 57 patients with a >10 pack-year smoking history: 26 had physiological evidence of COPD, and 31 had normal lung function (smoker control subjects). Bronchoscopy sampled the upper airways, lower airways, and environmental background. Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome, and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. Measurements and Main Results: Compared with smoker control subjects, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis, such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1, and MUC4 in mild-to-moderate COPD. Finally, in a preclinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury, revealing transcriptomic signatures similar to those observed in human subjects with COPD. Conclusions: Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.


Asunto(s)
Lesión Pulmonar , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Animales , Ratones , Disbiosis/complicaciones , ARN Ribosómico 16S , Enfermedad Pulmonar Obstructiva Crónica/genética , Inflamación/complicaciones , Lesión Pulmonar/complicaciones , Pulmón/patología
2.
ERJ Open Res ; 10(4)2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38978558

RESUMEN

Introduction: Mounting evidence indicates that an individual's humoral adaptive immune response plays a critical role in the setting of SARS-CoV-2 infection, and that the efficiency of the response correlates with disease severity. The relationship between the adaptive immune dynamics in the lower airways with those in the systemic circulation, and how these relate to an individual's clinical response to SARS-CoV-2 infection, are less understood and are the focus of this study. Material and methods: We investigated the adaptive immune response to SARS-CoV-2 in paired samples from the lower airways and blood from 27 critically ill patients during the first wave of the pandemic (median time from symptom onset to intubation 11 days). Measurements included clinical outcomes (mortality), bronchoalveolar lavage fluid (BALF) and blood specimen antibody levels, and BALF viral load. Results: While there was heterogeneity in the levels of the SARS-CoV-2-specific antibodies, we unexpectedly found that some BALF specimens displayed higher levels than the paired concurrent plasma samples, despite the known dilutional effects common in BALF samples. We found that survivors had higher levels of anti-spike, anti-spike-N-terminal domain and anti-spike-receptor-binding domain IgG antibodies in their BALF (p<0.05), while there was no such association with antibody levels in the systemic circulation. Discussion: Our data highlight the critical role of local adaptive immunity in the airways as a key defence mechanism against primary SARS-CoV-2 infection.

3.
Sci Rep ; 13(1): 2229, 2023 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-36755121

RESUMEN

Malignant pleural effusions (MPE) complicate malignancies and portend worse outcomes. MPE is comprised of various components, including immune cells, cancer cells, and cell-free DNA/RNA. There have been investigations into using these components to diagnose and prognosticate MPE. We hypothesize that the microbiome of MPE is unique and may be associated with diagnosis and prognosis. We compared the microbiota of MPE against microbiota of pleural effusions from non-malignant and paramalignant states. We collected a total of 165 pleural fluid samples from 165 subjects; Benign (n = 16), Paramalignant (n = 21), MPE-Lung (n = 57), MPE-Other (n = 22), and Mesothelioma (n = 49). We performed high throughput 16S rRNA gene sequencing on pleural fluid samples and controls. We showed that there are compositional differences among pleural effusions related to non-malignant, paramalignant, and malignant disease. Furthermore, we showed differential enrichment of bacterial taxa within MPE depending on the site of primary malignancy. Pleural fluid of MPE-Lung and Mesothelioma were associated with enrichment with oral and gut bacteria that are commonly thought to be commensals, including Rickettsiella, Ruminococcus, Enterococcus, and Lactobacillales. Mortality in MPE-Lung is associated with enrichment in Methylobacterium, Blattabacterium, and Deinococcus. These observations lay the groundwork for future studies that explore host-microbiome interactions and their influence on carcinogenesis.


Asunto(s)
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Microbiota , Derrame Pleural Maligno , Derrame Pleural , Humanos , ARN Ribosómico 16S/genética , Derrame Pleural Maligno/diagnóstico , Mesotelioma/diagnóstico , Mesotelioma/patología , Biomarcadores , Derrame Pleural/diagnóstico , Pronóstico , Microbiota/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/complicaciones
4.
Res Sq ; 2021 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-33791687

RESUMEN

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

5.
Cancer Discov ; 11(2): 293-307, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33177060

RESUMEN

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB-IV tumor-node-metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB-IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGNIFICANCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.See related commentary by Zitvogel and Kroemer, p. 224.This article is highlighted in the In This Issue feature, p. 211.


Asunto(s)
Adenocarcinoma/mortalidad , Disbiosis/complicaciones , Neoplasias Pulmonares/mortalidad , Adenocarcinoma/complicaciones , Adenocarcinoma/microbiología , Adenocarcinoma/secundario , Animales , Estudios de Cohortes , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/microbiología , Neoplasias Pulmonares/patología , Ratones , Ratones Transgénicos , Microbiota , Metástasis de la Neoplasia , Estadificación de Neoplasias , New York , Modelos de Riesgos Proporcionales , Análisis de Supervivencia
6.
Nat Microbiol ; 6(10): 1245-1258, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34465900

RESUMEN

Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.


Asunto(s)
Líquido del Lavado Bronquioalveolar/microbiología , COVID-19/terapia , Respiración Artificial , SARS-CoV-2/patogenicidad , Inmunidad Adaptativa , Adulto , Anciano , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Carga Bacteriana , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/virología , COVID-19/inmunología , COVID-19/microbiología , COVID-19/mortalidad , Enfermedad Crítica , Femenino , Hospitalización , Humanos , Inmunidad Innata , Masculino , Microbiota , Persona de Mediana Edad , Oportunidad Relativa , Pronóstico , Estudios Prospectivos , Sistema Respiratorio/inmunología , Sistema Respiratorio/microbiología , Sistema Respiratorio/virología , SARS-CoV-2/inmunología , Carga Viral
7.
medRxiv ; 2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33655261

RESUMEN

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

8.
Am J Med Genet ; 114(4): 429-35, 2002 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-11992566

RESUMEN

It has been demonstrated that the opioid peptide dynorphin plays a role in modulating responses to several psychoactive substances including cocaine. Our laboratory and others have found that mRNA levels of dynorphin in the caudate and putamen are elevated after acute or chronic cocaine exposure in rats. Recently, a 68-base pair (bp) repeat polymorphism within the core promoter region of the human prodynorphin gene has been reported to occur in alleles containing one, two, three, or four copies. This repeat contains a putative AP-1 transcription factor binding site; reporter gene constructs with three or four, but not one or two, copies of the tandem repeats were shown to be associated with increases in transcriptional activation in in vitro cellular assays. We hypothesize that this polymorphism may be associated with individual differences in vulnerability to cocaine dependence or abuse. From an ongoing study of the genetics of addiction, 174 subjects were studied, including individuals with a primary diagnosis (DSM-IV criteria) of cocaine dependence (N = 61) or abuse (N = 22), and controls with no history of any substance dependence or abuse (N = 91). We designed primers for polymerase chain reaction (PCR) to amplify sequences of the promoter region of the prodynorphin gene containing the repeat element. The association of alleles containing three or four repeats with cocaine dependence/abuse was examined. With data stratified by ethnic group, pooled relative risk (RR) with Mantel-Haenszel Chi square was calculated: RR = 0.59 (95% confidence interval 0.37-0.95), chi2 (1) = 4.14, P = 0.042. Our results suggest that this allelic variation at the promoter region of the prodynorphin gene (alleles with three or four repeats), which may result in enhanced transcription of the gene, may contribute to relative protection and decrease individual vulnerability to develop cocaine dependence or abuse.


Asunto(s)
Trastornos Relacionados con Cocaína/genética , Encefalinas/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Precursores de Proteínas/genética , Alelos , Secuencia de Bases , Trastornos Relacionados con Cocaína/etnología , ADN , Encefalinas/fisiología , Frecuencia de los Genes , Humanos , Datos de Secuencia Molecular , Precursores de Proteínas/fisiología , Secuencias Repetitivas de Ácidos Nucleicos
9.
Drug Alcohol Depend ; 69(2): 137-50, 2003 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-12609695

RESUMEN

The new Kreek-McHugh-Schluger-Kellogg scale ('KMSK scale') is designed to quantify self-exposure to opiates, cocaine, alcohol, and/or tobacco. Each section of the KMSK scale assesses the frequency, amount, and duration of use of a particular substance during the individual's period of greatest consumption. The scale also assesses the mode of use, whether the substance use is current or past, and whether each substance is the substance of choice. The administration time is under 5 min. In an initial validation study of this scale, 100 human subjects were administered the KMSK scale concurrently with the Structured Clinical Interview for DSM-IV (SCID-I DSM-IV version). The sensitivity and specificity were very good for opiates, cocaine, and alcohol use. In addition, the correlations between KMSK scores and the number of SCID-I criteria items met were excellent for opiates and cocaine and good for alcohol use. Nicotine dependence was not assessed in this study as there is no SCID-I nicotine criteria. These preliminary results show that the KMSK scale may have both construct validity similar to that of other established self-report measures and the potential to be an effective screening instrument for the assessment of a lifetime diagnosis of alcohol, opiate, or cocaine dependence.


Asunto(s)
Trastornos Relacionados con Sustancias/diagnóstico , Adulto , Femenino , Humanos , Masculino , Psicometría , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
10.
J Pers Assess ; 79(1): 73-84, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12227669

RESUMEN

An analysis of the relationship among the Personality Assessment Inventory (PAI; Morey, 1991, 1996) Drug Problems (DRG) scale scores, the Addiction Severity Index (ASI; McLellan et al., 1992) scores, and urine toxicology reports revealed that the PAI Drug Problem scale scores of 100 substance-using and substance-abusing men and women were distributed in a manner that was in agreement with the guidelines suggested by Morey (1991, 1996) in the PAI manual. There were significant correlations among the PAI DRG scale and the ASI scales related to frequency of use, negative consequences of use, and need and desire for treatment. Overall, higher scores did reflect both more serious involvements with drug use and more serious problems as a consequence of their involvement.


Asunto(s)
Metadona/uso terapéutico , Trastornos Relacionados con Opioides/diagnóstico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Inventario de Personalidad , Trastornos Relacionados con Sustancias/diagnóstico , Adulto , Femenino , Humanos , Masculino , Ciudad de Nueva York , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas
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