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Host lung gene expression patterns predict infectious etiology in a mouse model of pneumonia.

Evans SE, Tuvim MJ, Zhang J, Larson DT, García CD, Martinez-Pro S, Coombes KR, Dickey BF - Respir. Res. (2010)

Bottom Line: We observed robust, pathogen-specific gene expression patterns as early as 2 h after infection.Use of 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pulmonary Medicine, University of Texas-M D, Anderson Cancer Center, Houston, Texas, USA. seevans@mdanderson.org

ABSTRACT

Background: 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. This study assesses the capacity of the host gene expression response to infection to predict the presence and identity of lower respiratory pathogens without reliance on culture data.

Methods: Mice were inhalationally challenged with S. pneumoniae, P. aeruginosa, A. fumigatus or saline 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.

Results: We observed robust, pathogen-specific gene expression patterns as early as 2 h after infection. Use of 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.

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Related in: MedlinePlus

Survival following infectious challenges. (A) Using an experimental model of inhalational pneumonia in BALB/c mice, P. aeruginosa and S. pneumoniae both induced consistent mortality >80%, while mice challenged with A. fumigatus or PBS (sham) had 100% survival. (B) Mice treated with cyclophosphamide and cortisol prior to infection also consistently succumbed to A. fumigatus challenge, substantiating the effective delivery of pathogens to the mice (N = 10 mice/group, *p = 0.0007 vs. A. fumigatus, **p = 0.0001 vs. A. fumigatus, †p < 0.0001 vs. A. fumigatus).
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Figure 1: Survival following infectious challenges. (A) Using an experimental model of inhalational pneumonia in BALB/c mice, P. aeruginosa and S. pneumoniae both induced consistent mortality >80%, while mice challenged with A. fumigatus or PBS (sham) had 100% survival. (B) Mice treated with cyclophosphamide and cortisol prior to infection also consistently succumbed to A. fumigatus challenge, substantiating the effective delivery of pathogens to the mice (N = 10 mice/group, *p = 0.0007 vs. A. fumigatus, **p = 0.0001 vs. A. fumigatus, †p < 0.0001 vs. A. fumigatus).

Mentions: Consistent with our prior observations [29-31], our bacterial pneumonia model yielded highly reproducible mortality (Figure 1A). No mortality was observed following fungal challenges or sham treatment. We confirmed delivery of infective conidia through the observation of highly reproducible mortality at the same inoculum for immunosuppressed mice (Figure 1B), and serial dilution culture of lung homogenates showed deposition of approximately 3 × 106 conidia per A. fumigatus-challenged mouse.


Host lung gene expression patterns predict infectious etiology in a mouse model of pneumonia.

Evans SE, Tuvim MJ, Zhang J, Larson DT, García CD, Martinez-Pro S, Coombes KR, Dickey BF - Respir. Res. (2010)

Survival following infectious challenges. (A) Using an experimental model of inhalational pneumonia in BALB/c mice, P. aeruginosa and S. pneumoniae both induced consistent mortality >80%, while mice challenged with A. fumigatus or PBS (sham) had 100% survival. (B) Mice treated with cyclophosphamide and cortisol prior to infection also consistently succumbed to A. fumigatus challenge, substantiating the effective delivery of pathogens to the mice (N = 10 mice/group, *p = 0.0007 vs. A. fumigatus, **p = 0.0001 vs. A. fumigatus, †p < 0.0001 vs. A. fumigatus).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2914038&req=5

Figure 1: Survival following infectious challenges. (A) Using an experimental model of inhalational pneumonia in BALB/c mice, P. aeruginosa and S. pneumoniae both induced consistent mortality >80%, while mice challenged with A. fumigatus or PBS (sham) had 100% survival. (B) Mice treated with cyclophosphamide and cortisol prior to infection also consistently succumbed to A. fumigatus challenge, substantiating the effective delivery of pathogens to the mice (N = 10 mice/group, *p = 0.0007 vs. A. fumigatus, **p = 0.0001 vs. A. fumigatus, †p < 0.0001 vs. A. fumigatus).
Mentions: Consistent with our prior observations [29-31], our bacterial pneumonia model yielded highly reproducible mortality (Figure 1A). No mortality was observed following fungal challenges or sham treatment. We confirmed delivery of infective conidia through the observation of highly reproducible mortality at the same inoculum for immunosuppressed mice (Figure 1B), and serial dilution culture of lung homogenates showed deposition of approximately 3 × 106 conidia per A. fumigatus-challenged mouse.

Bottom Line: We observed robust, pathogen-specific gene expression patterns as early as 2 h after infection.Use of 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pulmonary Medicine, University of Texas-M D, Anderson Cancer Center, Houston, Texas, USA. seevans@mdanderson.org

ABSTRACT

Background: 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. This study assesses the capacity of the host gene expression response to infection to predict the presence and identity of lower respiratory pathogens without reliance on culture data.

Methods: Mice were inhalationally challenged with S. pneumoniae, P. aeruginosa, A. fumigatus or saline 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.

Results: We observed robust, pathogen-specific gene expression patterns as early as 2 h after infection. Use of 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.

Show MeSH
Related in: MedlinePlus