A Host Transcriptional Signature for Presymptomatic Detection of Infection in Humans Exposed to Influenza H1N1 or H3N2

Christopher W. Woods equal contributor mail,
Micah T. McClain equal contributor,
Minhua Chen,
Aimee K. Zaas,
Bradly P. Nicholson,
Jay Varkey,
Timothy Veldman,
Stephen F. Kingsmore,
Yongsheng Huang,
Robert Lambkin-Williams,
Anthony G. Gilbert,
Alfred O. Hero III,
Elizabeth Ramsburg,
[ ... ],
Geoffrey S. Ginsburg mail
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Abstract

There is great potential for host-based gene expression analysis to impact the early diagnosis of infectious diseases. In particular, the influenza pandemic of 2009 highlighted the challenges and limitations of traditional pathogen-based testing for suspected upper respiratory viral infection. We inoculated human volunteers with either influenza A (A/Brisbane/59/2007 (H1N1) or A/Wisconsin/67/2005 (H3N2)), and assayed the peripheral blood transcriptome every 8 hours for 7 days. Of 41 inoculated volunteers, 18 (44%) developed symptomatic infection. Using unbiased sparse latent factor regression analysis, we generated a gene signature (or factor) for symptomatic influenza capable of detecting 94% of infected cases. This gene signature is detectable as early as 29 hours post-exposure and achieves maximal accuracy on average 43 hours (p = 0.003, H1N1) and 38 hours (p-value = 0.005, H3N2) before peak clinical symptoms. In order to test the relevance of these findings in naturally acquired disease, a composite influenza A signature built from these challenge studies was applied to Emergency Department patients where it discriminates between swine-origin influenza A/H1N1 (2009) infected and non-infected individuals with 92% accuracy. The host genomic response to Influenza infection is robust and may provide the means for detection before typical clinical symptoms are apparent.

Citation: Woods CW, McClain MT, Chen M, Zaas AK, Nicholson BP, et al. (2013) A Host Transcriptional Signature for Presymptomatic Detection of Infection in Humans Exposed to Influenza H1N1 or H3N2. PLoS ONE 8(1): e52198. doi:10.1371/journal.pone.0052198
Editor: Herman Tse, The University of Hong Kong, Hong Kong
Received: June 25, 2012; Accepted: November 15, 2012; Published: January 9, 2013
Copyright: © 2013 Woods et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Funding for this study was provided by the US Defense Advanced Research Projects Agency (DARPA) through contract N66001-07-C-2024 (P.I., Ginsburg). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The viral signature developed from this work is indeed the subject of a pending patent held by Dr's Ginsburg, Woods, Zaas, Lucas, Hero and Carin: PCT Application No. PCT/US2010/036257, “METHODS OF IDENTIFYING INFECTIOUS DISEASE AND ASSAYS FOR IDENTIFYING INFECTIOUS DISEASE” (File date 5/2010). However, this does not conflict with PLOS One policies and the research data will be made publically available according to the journal”s policy. Dr. Gilbert and Dr. Lambkin-Williams are employed by Retroscreen Virology, as mentioned in the Authors” affiliations portion of the manuscript. This company was involved in oversight of the conduction of the viral challenge studies utilized in the current manuscript. This does not in any way alter the authors' adherence to all of the PLOS ONE policies on sharing data and materials.
* E-mail: chris.woods@duke.edu (CW); geoffrey.ginsburg@duke.edu (GG)
# These authors contributed equally to this work.