Host lung gene expression patterns predict the etiology of infectious pneumonias
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE15869 | GEO | 2009/04/29
SECONDARY ACCESSION(S): PRJNA116975
REPOSITORIES: GEO
Similar Datasets
Project description:Rationale: Lower respiratory tract infections continue to exact unacceptable worldwide mortality, often because the infecting pathogen cannot be identified. The respiratory epithelia provide protection from pneumonias through organism-specific generation of antimicrobial products, offering potential insight into the identity of infecting pathogens. Objective: This study assesses the capacity of the host gene expression response to infection to predict lower respiratory pathogens without reliance on culture data. Methods: Mice were inhalationally challenged with S. pneumoniae, P. aeruginosa, A. fumigatus or PBS prior to whole genome gene expression microarray analysis of their pulmonary parenchyma. Characteristic gene expression patterns for each condition were identified, allowing the derivation of prediction rules for each pathogen. After confirming the predictive capacity of gene expression data in blinded challenges, a computerized algorithm was devised to predict the infectious conditions of subsequent subjects. Measurements and Main Results: We observed robust, pathogen-specific gene expression patterns as early as 2 h after infection. We were able to develop a predictive model that used a limited number of specifically regulated transcripts to discriminate perfectly among infecting pathogens in the training data. Validation trials using an algorithmic decision tree revealed 94.4% diagnostic accuracy when discerning the presence of bacterial infection. The model subsequently differentiated between bacterial pathogens with 71.4% accuracy and between non-bacterial conditions with 70.0% accuracy, both far exceeding the expected diagnostic yield of standard culture-based bronchoscopy with bronchoalveolar lavage. Conclusions: These data substantiate the specificity of the pulmonary innate immune response and support the feasibility of a gene expression-based clinical tool for pneumonia diagnosis. Keywords: pathogen- and time-dependent host lung gene expression changes in pneumonia Mouse lungs were removed 6 h after challenge with P. aeruginosa, S. pneumoniae, A. fumigatus or sham (PBS), RNA was collected from leukoreduced lung homogenates, then cRNA was amplified and hybridized to Illumina Sentrix mouse-6 gene expression arrays v1.1. Gene expression data was analyzed to determine if there were distinct patterns of host trasnscription that corresponded with a specific infection.
2009-04-29 | E-GEOD-15869 | biostudies-arrayexpress
Project description:<p>Accurate tests for microbiologic diagnosis of lower respiratory tract infections (LRTI) are needed. Gene expression profiling of whole blood represents a powerful new approach for analysis of the host response during respiratory infection that can be used to supplement pathogen detection testing. Using qPCR, we prospectively validated the differential expression of 10 genes previously shown to discriminate bacterial and non-bacterial LRTI confirming the utility of this approach. In addition, a novel approach using RNAseq analysis identified 141 genes differentially expressed in LRTI subjects with bacterial infection. Using "pathway-informed" dimension reduction, we identified a novel 11 gene set (selected from lymphocyte, α-linoleic acid metabolism, and IGF regulation pathways) and demonstrated a predictive accuracy for bacterial LRTI (nested CV-AUC=0.87). RNAseq represents a new and an unbiased tool to evaluate host gene expression for the diagnosis of LRTI.</p>
| phs001248 | dbGaP
Project description:Pneumonia is a serious problem worldwide. We recently demonstrated that innate defense mechanisms of the lung are highly inducible against pneumococcal pneumonia. To determine the breadth of protection conferred by stimulation of lung mucosal innate immunity, and to identify cells and signaling pathways activated by this treatment, mice were treated with an aerosolized bacterial lysate, then challenged with lethal doses of bacterial and fungal pathogens. Mice were highly protected against a broad array of Gram-positive, Gram-negative, and Class A bioterror bacterial pathogens, and Aspergillus fumigatus. Protection was associated with rapid pathogen killing within the lungs, and this effect was recapitulated in vitro using a respiratory epithelial cell line. Gene expression analysis of lung tissue showed marked activation of NF-kappaB, Type I and II interferon, and antifungal Card9-Bcl10-Malt1 pathways. Cytokines were the most strongly induced genes, but the inflammatory cytokines TNF and IL-6 were not required for protection. Lung-expressed antimicrobial peptides were also highly upregulated. Taken together, stimulated innate resistance (StIR) appears to occur through the activation of multiple host defense signaling pathways in lung epithelial cells, inducing rapid pathogen killing, and conferring broad protection against virulent bacterial and fungal pathogens. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value for protection of patients with neutropenia or impaired adaptive immunity against opportunistic pneumonia, and for defense of immunocompetent subjects against a bioterror threat or epidemic respiratory infection. Keywords: differential gene expression; time course; innate immunity; pneumonia; immunocompromised host; lung epithelium Gene expression patterns in mouse lung homogenates were analyzed 2h after exposure to aerosolized PBS (Sham treatment), 2h after exposure to aerosolized NTHi lysate or 4h after exposure to aerosolized NTHi lysate. Each group consisted of six mice.
2010-06-24 | E-GEOD-13740 | biostudies-arrayexpress
Project description:Pneumonia is a serious problem worldwide. We recently demonstrated that innate defense mechanisms of the lung are highly inducible against pneumococcal pneumonia. To determine the breadth of protection conferred by stimulation of lung mucosal innate immunity, and to identify cells and signaling pathways activated by this treatment, mice were treated with an aerosolized bacterial lysate, then challenged with lethal doses of bacterial and fungal pathogens. Mice were highly protected against a broad array of Gram-positive, Gram-negative, and Class A bioterror bacterial pathogens, and Aspergillus fumigatus. Protection was associated with rapid pathogen killing within the lungs, and this effect was recapitulated in vitro using a respiratory epithelial cell line. Gene expression analysis of lung tissue showed marked activation of NF-kappa-B, Type I and II interferon, and antifungal Card9-Bcl10-Malt1 pathways. Cytokines were the most strongly induced genes, but the inflammatory cytokines TNF and IL-6 were not required for protection. Lung-expressed antimicrobial peptides were also highly upregulated. Taken together, stimulated innate resistance (StIR) appears to occur through the activation of multiple host defense signaling pathways in lung epithelial cells, inducing rapid pathogen killing, and conferring broad protection against virulent bacterial and fungal pathogens. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value for protection of patients with neutropenia or impaired adaptive immunity against opportunistic pneumonia, and for defense of immunocompetent subjects against a bioterror threat or epidemic respiratory infection. Keywords: Differential expression, innate immunity, pneumonia, immunocompromised host; lung epithelium, in vitro, MLE-15 cells were treated with sham (PBS), NTHi lysate (100 ug/ml) or EF2505-III (40 ug/ml). 4 unique samples per group. Treated for 2 hours. Hybridized to Illumina Sentrix Mouse-6 v1.1 Beadhips.
2010-06-24 | E-GEOD-13685 | biostudies-arrayexpress
Project description:Introduction: Diagnosis of severe influenza pneumonia remains challenging because of the lack of correlation between presence of influenza virus and patient’s clinical status. We conducted gene expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure (e.g. bacterial pneumonia, non-infective systemic inflammatory response syndrome). Methods: Whole blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene expression beadarrays. Differentially expressed genes were determined by linear mixed model analysis and over-represented biological pathways determined using GeneGo MetaCore. Results: The gene expression profile of H1N1 influenza A pneumonia was distinctly different from bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene expression profile is characterized by up-regulation of genes from cell cycle regulation, apoptosis and DNA-damage response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene expression profile of influenza infection persisted through five days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection who subsequently developed bacterial co-infection, the influenza gene-expression signature remained unaltered, despite the presence of a super-imposed bacterial infection. Conclusions: The whole blood expression profiling data indicates that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed up identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly. Daily PAXgene samples for up to 5 days for; influenza A pneumonia patients (n=8), bacterial pneumonia patients (n=16), mixed bacterial and influenza A pneumonia patients (n=3), systemic inflammatory response patients (SIRS, n=13). Days 1 and 5 PAXgene samples for healthy control individuals
2012-08-14 | E-GEOD-40012 | biostudies-arrayexpress
Project description:With annually 2.56 million deaths worldwide, pneumonia is one of the leading causes of death. Most frequent causative pathogens are Streptococcus pneumoniae and influenza A virus. Lately, the interaction between pathogens, the host and its microbiome gained more attention. A healthy microbiome is known to enhance the immune response towards pathogens, however, our knowledge on how infections affect the microbiome is still scarce. In this study, a meta-omics approach was used to investigate the impact of S. pneumoniae and influenza A virus infection on structure and function of the respiratory and gastrointestinal microbiomes of mice. In particular, the taxonomic composition of the respiratory microbiome was less affected by bacterial colonization and viral infection compared to S. pneumoniae infection. Pneumococcal pneumonia led to reduction of bacterial families and lower diversity in the respiratory microbiome, whereas diversity/richness was unaffected following H1N1 infection. Within the gastrointestinal microbiome we found exclusive changes in structure and function depending on the pneumonia inducing pathogen. Exemplarily, increased abundance of Akkermansiaceae and Spirochaetaceae, as well as decreased amounts of Clostridiaceae in response to S. pneumoniae infection, while increased presence of Enterococcaceae and Staphylococcaceae was specific for viral-induced pneumonia. Investigation of the intestinal microbiomes functional composition revealed reduced expression of flagellin and rubrerythrin and increased levels of ATPase during pneumococcal infection, while increased amounts of acetyl-CoA acetyltransferase and, enoyl-CoA transferase were unique after H1N1 infection. The identification of specific taxonomical and functional profiles during infection with a respective pathogen could deliver new insights in the role of the microbiome during disease and be beneficial for discrimination of pneumococcal- or viral-induced pneumonia.
2023-03-24 | PXD036129 | Pride
Project description:With annually 2.56 million deaths worldwide, pneumonia is one of the leading causes of death. Most frequent causative pathogens are Streptococcus pneumoniae and influenza A virus. Lately, the interaction between pathogens, the host and its microbiome gained more attention. A healthy microbiome is known to enhance the immune response towards pathogens, however, our knowledge on how infections affect the microbiome is still scarce. In this study, a meta-omics approach was used to investigate the impact of S. pneumoniae and influenza A virus infection on structure and function of the respiratory and gastrointestinal microbiomes of mice. In particular, the taxonomic composition of the respiratory microbiome was less affected by bacterial colonization and viral infection compared to S. pneumoniae infection. Pneumococcal pneumonia led to reduction of bacterial families and lower diversity in the respiratory microbiome, whereas diversity/richness was unaffected following H1N1 infection. Within the gastrointestinal microbiome we found exclusive changes in structure and function depending on the pneumonia inducing pathogen. Exemplarily, increased abundance of Akkermansiaceae and Spirochaetaceae, as well as decreased amounts of Clostridiaceae in response to S. pneumoniae infection, while increased presence of Enterococcaceae and Staphylococcaceae was specific for viral-induced pneumonia. Investigation of the intestinal microbiomes functional composition revealed reduced expression of flagellin and rubrerythrin and increased levels of ATPase during pneumococcal infection, while increased amounts of acetyl-CoA acetyltransferase and, enoyl-CoA transferase were unique after H1N1 infection. The identification of specific taxonomical and functional profiles during infection with a respective pathogen could deliver new insights in the role of the microbiome during disease and be beneficial for discrimination of pneumococcal- or viral-induced pneumonia.
2023-03-24 | PXD036014 | Pride
Project description:With annually 2.56 million deaths worldwide, pneumonia is one of the leading causes of death. Most frequent causative pathogens are Streptococcus pneumoniae and influenza A virus. Lately, the interaction between pathogens, the host and its microbiome gained more attention. A healthy microbiome is known to enhance the immune response towards pathogens, however, our knowledge on how infections affect the microbiome is still scarce. In this study, a meta-omics approach was used to investigate the impact of S. pneumoniae and influenza A virus infection on structure and function of the respiratory and gastrointestinal microbiomes of mice. In particular, the taxonomic composition of the respiratory microbiome was less affected by bacterial colonization and viral infection compared to S. pneumoniae infection. Pneumococcal pneumonia led to reduction of bacterial families and lower diversity in the respiratory microbiome, whereas diversity/richness was unaffected following H1N1 infection. Within the gastrointestinal microbiome we found exclusive changes in structure and function depending on the pneumonia inducing pathogen. Exemplarily, increased abundance of Akkermansiaceae and Spirochaetaceae, as well as decreased amounts of Clostridiaceae in response to S. pneumoniae infection, while increased presence of Enterococcaceae and Staphylococcaceae was specific for viral-induced pneumonia. Investigation of the intestinal microbiomes functional composition revealed reduced expression of flagellin and rubrerythrin and increased levels of ATPase during pneumococcal infection, while increased amounts of acetyl-CoA acetyltransferase and, enoyl-CoA transferase were unique after H1N1 infection. The identification of specific taxonomical and functional profiles during infection with a respective pathogen could deliver new insights in the role of the microbiome during disease and be beneficial for discrimination of pneumococcal- or viral-induced pneumonia.
2023-03-24 | PXD036279 | Pride
Project description:With annually 2.56 million deaths worldwide, pneumonia is one of the leading causes of death. Most frequent causative pathogens are Streptococcus pneumoniae and influenza A virus. Lately, the interaction between pathogens, the host and its microbiome gained more attention. A healthy microbiome is known to enhance the immune response towards pathogens, however, our knowledge on how infections affect the microbiome is still scarce. In this study, a meta-omics approach was used to investigate the impact of S. pneumoniae and influenza A virus infection on structure and function of the respiratory and gastrointestinal microbiomes of mice. In particular, the taxonomic composition of the respiratory microbiome was less affected by bacterial colonization and viral infection compared to S. pneumoniae infection. Pneumococcal pneumonia led to reduction of bacterial families and lower diversity in the respiratory microbiome, whereas diversity/richness was unaffected following H1N1 infection. Within the gastrointestinal microbiome we found exclusive changes in structure and function depending on the pneumonia inducing pathogen. Exemplarily, increased abundance of Akkermansiaceae and Spirochaetaceae, as well as decreased amounts of Clostridiaceae in response to S. pneumoniae infection, while increased presence of Enterococcaceae and Staphylococcaceae was specific for viral-induced pneumonia. Investigation of the intestinal microbiomes functional composition revealed reduced expression of flagellin and rubrerythrin and increased levels of ATPase during pneumococcal infection, while increased amounts of acetyl-CoA acetyltransferase and, enoyl-CoA transferase were unique after H1N1 infection. The identification of specific taxonomical and functional profiles during infection with a respective pathogen could deliver new insights in the role of the microbiome during disease and be beneficial for discrimination of pneumococcal- or viral-induced pneumonia.
2023-03-24 | PXD036115 | Pride
Project description:Pneumonia is a serious problem worldwide. We recently demonstrated that innate defense mechanisms of the lung are highly inducible against pneumococcal pneumonia. To determine the breadth of protection conferred by stimulation of lung mucosal innate immunity, and to identify cells and signaling pathways activated by this treatment, mice were treated with an aerosolized bacterial lysate, then challenged with lethal doses of bacterial and fungal pathogens. Mice were highly protected against a broad array of Gram-positive, Gram-negative, and Class A bioterror bacterial pathogens, and Aspergillus fumigatus. Protection was associated with rapid pathogen killing within the lungs, and this effect was recapitulated in vitro using a respiratory epithelial cell line. Gene expression analysis of lung tissue showed marked activation of NF-kappaB, Type I and II interferon, and antifungal Card9-Bcl10-Malt1 pathways. Cytokines were the most strongly induced genes, but the inflammatory cytokines TNF and IL-6 were not required for protection. Lung-expressed antimicrobial peptides were also highly upregulated. Taken together, stimulated innate resistance (StIR) appears to occur through the activation of multiple host defense signaling pathways in lung epithelial cells, inducing rapid pathogen killing, and conferring broad protection against virulent bacterial and fungal pathogens. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value for protection of patients with neutropenia or impaired adaptive immunity against opportunistic pneumonia, and for defense of immunocompetent subjects against a bioterror threat or epidemic respiratory infection. Keywords: differential gene expression; time course; innate immunity; pneumonia; immunocompromised host; lung epithelium
2008-11-26 | GSE13740 | GEO