PLOS ONE: Gene Expression-Based Classifiers Identify Staphylococcus aureus Infection in Mice and Humans
Research Article
Gene Expression-Based Classifiers Identify Staphylococcus aureus Infection in Mice and Humans
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Abstract
Staphylococcus aureus causes a spectrum of human infection. Diagnostic delays and uncertainty lead to treatment delays and inappropriate antibiotic use. A growing literature suggests the host’s inflammatory response to the pathogen represents a potential tool to improve upon current diagnostics. The hypothesis of this study is that the host responds differently to S. aureus than to E. coli infection in a quantifiable way, providing a new diagnostic avenue. This study uses Bayesian sparse factor modeling and penalized binary regression to define peripheral blood gene-expression classifiers of murine and human S. aureus infection. The murine-derived classifier distinguished S. aureus infection from healthy controls and Escherichia coli-infected mice across a range of conditions (mouse and bacterial strain, time post infection) and was validated in outbred mice (AUC>0.97). A S. aureus classifier derived from a cohort of 94 human subjects distinguished S. aureus blood stream infection (BSI) from healthy subjects (AUC 0.99) and E. coli BSI (AUC 0.84). Murine and human responses to S. aureus infection share common biological pathways, allowing the murine model to classify S. aureus BSI in humans (AUC 0.84). Both murine and human S. aureus classifiers were validated in an independent human cohort (AUC 0.95 and 0.92, respectively). The approach described here lends insight into the conserved and disparate pathways utilized by mice and humans in response to these infections. Furthermore, this study advances our understanding of S. aureus infection; the host response to it; and identifies new diagnostic and therapeutic avenues.Citation: Ahn SH, Tsalik EL, Cyr DD, Zhang Y, van Velkinburgh JC, et al. (2013) Gene Expression-Based Classifiers Identify Staphylococcus aureus Infection in Mice and Humans. PLoS ONE 8(1): e48979. doi:10.1371/journal.pone.0048979
Editor: Michael Otto, National Institutes of Health, United States of America
Received: August 20, 2012; Accepted: September 27, 2012; Published: January 9, 2013
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: This work was supported by R01-AI068804 and K24-AI093969 from the National Institute of Allergy and Infectious Diseases (VGF), 5U01AI066569-05 and 3U01AI066569-05S1 from the National Institute of Allergy and Infectious Diseases (SFK), and the Wallace H. Coulter Foundation (AKZ and GSG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have read the journal’s policy and have the following conflicts: CBC and CWW have served as consultants for bioMerieux Inc. ELT, CWW, and GSG received research funding from Novartis Vaccines and Diagnostics, Inc. In the past 12 months, CWW has served as a consultant to Becton, Dickinson and Company, and Gilead Sciences; and has received research or grant support from Cubist Pharmaceuticals, Novartis Pharmaceuticals, and Roche Molecular Diagnostics. ELT is supported by a Veterans Affairs Career Development Award. In the past 12 months, VGF has received grant or research support from Astellas Pharma US, Merck, Theravance, Cerexa, Pfizer, Novartis, MedImmune, Advance Liquid Logic, and the National Institutes of Health; has served as a consultant for Achaogen, Merck, Novartis, Pfizer, NovaDigm Therapeutics, The Medicines Company, Durata Therapeutics, Galderma, and Biosynexus; and is on the Advisory Committee for Cubist Pharmaceuticals. AKZ is a consultant for Covance. EPR receives research support from Agennix AG, Alere Corporation, and National Institutes of Health; and has previously served as a consultant for Agennix AG, Eisai Pharmaceuticals, Idaho Technology, AstraZeneca, Masimo, and Sangard. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.
* E-mail: Geoffrey.ginsburg@duke.edu (GSG); vance.fowler@duke.edu (VGF)
# These authors contributed equally to this work.
Editor: Michael Otto, National Institutes of Health, United States of America
Received: August 20, 2012; Accepted: September 27, 2012; Published: January 9, 2013
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: This work was supported by R01-AI068804 and K24-AI093969 from the National Institute of Allergy and Infectious Diseases (VGF), 5U01AI066569-05 and 3U01AI066569-05S1 from the National Institute of Allergy and Infectious Diseases (SFK), and the Wallace H. Coulter Foundation (AKZ and GSG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have read the journal’s policy and have the following conflicts: CBC and CWW have served as consultants for bioMerieux Inc. ELT, CWW, and GSG received research funding from Novartis Vaccines and Diagnostics, Inc. In the past 12 months, CWW has served as a consultant to Becton, Dickinson and Company, and Gilead Sciences; and has received research or grant support from Cubist Pharmaceuticals, Novartis Pharmaceuticals, and Roche Molecular Diagnostics. ELT is supported by a Veterans Affairs Career Development Award. In the past 12 months, VGF has received grant or research support from Astellas Pharma US, Merck, Theravance, Cerexa, Pfizer, Novartis, MedImmune, Advance Liquid Logic, and the National Institutes of Health; has served as a consultant for Achaogen, Merck, Novartis, Pfizer, NovaDigm Therapeutics, The Medicines Company, Durata Therapeutics, Galderma, and Biosynexus; and is on the Advisory Committee for Cubist Pharmaceuticals. AKZ is a consultant for Covance. EPR receives research support from Agennix AG, Alere Corporation, and National Institutes of Health; and has previously served as a consultant for Agennix AG, Eisai Pharmaceuticals, Idaho Technology, AstraZeneca, Masimo, and Sangard. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.
* E-mail: Geoffrey.ginsburg@duke.edu (GSG); vance.fowler@duke.edu (VGF)
# These authors contributed equally to this work.
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