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      Temporal Dynamics of Host Molecular Responses Differentiate Symptomatic and Asymptomatic Influenza A Infection

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          Abstract

          Exposure to influenza viruses is necessary, but not sufficient, for healthy human hosts to develop symptomatic illness. The host response is an important determinant of disease progression. In order to delineate host molecular responses that differentiate symptomatic and asymptomatic Influenza A infection, we inoculated 17 healthy adults with live influenza (H3N2/Wisconsin) and examined changes in host peripheral blood gene expression at 16 timepoints over 132 hours. Here we present distinct transcriptional dynamics of host responses unique to asymptomatic and symptomatic infections. We show that symptomatic hosts invoke, simultaneously, multiple pattern recognition receptors-mediated antiviral and inflammatory responses that may relate to virus-induced oxidative stress. In contrast, asymptomatic subjects tightly regulate these responses and exhibit elevated expression of genes that function in antioxidant responses and cell-mediated responses. We reveal an ab initio molecular signature that strongly correlates to symptomatic clinical disease and biomarkers whose expression patterns best discriminate early from late phases of infection. Our results establish a temporal pattern of host molecular responses that differentiates symptomatic from asymptomatic infections and reveals an asymptomatic host-unique non-passive response signature, suggesting novel putative molecular targets for both prognostic assessment and ameliorative therapeutic intervention in seasonal and pandemic influenza.

          Author Summary

          The transcriptional responses of human hosts towards influenza viral pathogens are important for understanding virus-mediated immunopathology. Despite great advances gained through studies using model organisms, the complete temporal host transcriptional responses in a natural human system are poorly understood. In a human challenge study using live influenza (H3N2/Wisconsin) viruses, we conducted a clinically uninformed (unsupervised) factor analysis on gene expression profiles and established an ab initio molecular signature that strongly correlates to symptomatic clinical disease. This is followed by the identification of 42 biomarkers whose expression patterns best differentiate early from late phases of infection. In parallel, a clinically informed (supervised) analysis revealed over-stimulation of multiple viral sensing pathways in symptomatic hosts and linked their temporal trajectory with development of diverse clinical signs and symptoms. The resultant inflammatory cytokine profiles were shown to contribute to the pathogenesis because their significant increase preceded disease manifestation by 36 hours. In subclinical asymptomatic hosts, we discovered strong transcriptional regulation of genes involved in inflammasome activation, genes encoding virus interacting proteins, and evidence of active anti-oxidant and cell-mediated innate immune response. Taken together, our findings offer insights into influenza virus-induced pathogenesis and provide a valuable tool for disease monitoring and management in natural environments.

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          Most cited references51

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.

            Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
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              Inflammatory bowel disease.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                August 2011
                August 2011
                25 August 2011
                : 7
                : 8
                : e1002234
                Affiliations
                [1 ]Center for Computational Biology and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America
                [2 ]Department of Statistics, University of Michigan, Ann Arbor, Michigan, United States of America
                [3 ]Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America
                [4 ]Department of Medicine, Duke University, Durham, North Carolina, United States of America
                [5 ]Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America
                [6 ]IRIT/INP-ENSEEIHT, University of Toulouse, Toulouse, France
                [7 ]Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America
                [8 ]Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America
                [9 ]Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia, United States of America
                [10 ]Department of Electrical and Computer Engineering, Duke University, Durham, North Carolina, United States of America
                [11 ]Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri, United States of America
                [12 ]Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, Michigan, United States of America
                University of California San Diego and The Scripps Research Institute, United States of America
                Author notes

                Conceived and designed the experiments: AKZ TV CWW GSG BN. Performed the experiments: AKZ JBV CWW NCØ. Analyzed the data: YH MTM AOH. Contributed reagents/materials/analysis tools: AR ND PJW LC AOH. Wrote the paper: YH AKZ MTM SK CWW GSG AOH.

                Article
                PGENETICS-D-11-00033
                10.1371/journal.pgen.1002234
                3161909
                21901105
                69015a0e-8f69-4827-8225-863497f327c6
                Huang 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.
                History
                : 5 January 2011
                : 28 June 2011
                Page count
                Pages: 17
                Categories
                Research Article
                Biology
                Computational Biology
                Microarrays
                Genomics
                Genome Expression Analysis
                Immunology
                Immune System
                Cytokines
                Immunity
                Immune Activation
                Immune Defense
                Immune Tolerance
                Immunity to Infections
                Inflammation
                Innate Immunity
                Immune Response
                Immunopathology
                Microbiology
                Virology
                Antivirals
                Viral Disease Diagnosis
                Viral Immune Evasion
                Virulence Factors and Mechanisms
                Host-Pathogen Interaction
                Mathematics
                Statistics

                Genetics
                Genetics

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