Integrated, Multi-cohort Analysis Identifies Conserved Transcriptional Signatures across Multiple Respiratory Viruses

Summary Respiratory viral infections are a significant burden to healthcare worldwide. Many whole genome expression profiles have identified different respiratory viral infection signatures, but these have not translated to clinical practice. Here, we performed two integrated, multi-cohort analyses of publicly available transcriptional data of viral infections. First, we identified a common host signature across different respiratory viral infections that could distinguish (1) individuals with viral infections from healthy controls and from those with bacterial infections, and (2) symptomatic from asymptomatic subjects prior to symptom onset in challenge studies. Second, we identified an influenza-specific host response signature that (1) could distinguish influenza-infected samples from those with bacterial and other respiratory viral infections, (2) was a diagnostic and prognostic marker in influenza-pneumonia patients and influenza challenge studies, and (3) was predictive of response to influenza vaccine. Our results have applications in the diagnosis, prognosis, and identification of drug targets in viral infections.

[1]  Sandra Diederich,et al.  Temporal- and Strain-Specific Host MicroRNA Molecular Signatures Associated with Swine-Origin H1N1 and Avian-Origin H7N7 Influenza A Virus Infection , 2012, Journal of Virology.

[2]  P. Khatri,et al.  A systems biology approach for pathway level analysis. , 2007, Genome research.

[3]  L. Carin,et al.  Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans. , 2009, Cell host & microbe.

[4]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[5]  J. Banchereau,et al.  Gene expression patterns in blood leukocytes discriminate patients with acute infections. , 2007, Blood.

[6]  Dennis B. Troup,et al.  NCBI GEO: mining millions of expression profiles—database and tools , 2004, Nucleic Acids Res..

[7]  Molly S Bray,et al.  Integrative genomic analysis of the human immune response to influenza vaccination , 2013, eLife.

[8]  Purvesh Khatri,et al.  A meta-analysis of lung cancer gene expression identifies PTK7 as a survival gene in lung adenocarcinoma. , 2014, Cancer research.

[9]  N. Warner,et al.  Major Causes of Antiviral drug Resistance and Implications for Treatment of Hepatitis B virus Monoinfection and Coinfection with HIV , 2006, Antiviral therapy.

[10]  Mark M. Davis,et al.  Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination , 2013, Proceedings of the National Academy of Sciences.

[11]  Mark M. Davis,et al.  Apoptosis and other immune biomarkers predict influenza vaccine responsiveness , 2014, Molecular Systems Biology.

[12]  O. Ramilo,et al.  Plasticity and Virus Specificity of the Airway Epithelial Cell Immune Response during Respiratory Virus Infection , 2012, Journal of Virology.

[13]  L. Santos‐Argumedo,et al.  CD38 is expressed selectively during the activation of a subset of mature T cells with reduced proliferation but improved potential to produce cytokines , 2005, Journal of leukocyte biology.

[14]  R. Sugrue,et al.  Activation of Type I and III Interferon Signalling Pathways Occurs in Lung Epithelial Cells Infected with Low Pathogenic Avian Influenza Viruses , 2012, PloS one.

[15]  Renji Reghunathan,et al.  Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome , 2005, BMC Immunology.

[16]  R. Fisher Statistical methods for research workers , 1927, Protoplasma.

[17]  C. Rice,et al.  Interferon-stimulated genes and their antiviral effector functions , 2011, Current Opinion in Virology.

[18]  Richard A. Young,et al.  Insights into host responses against pathogens from transcriptional profiling , 2005, Nature Reviews Microbiology.

[19]  Sandra Romero-Steiner,et al.  Molecular signatures of antibody responses derived from a systems biology study of five human vaccines , 2022 .

[20]  Purvesh Khatri,et al.  A System Biology Approach for the Steady-State Analysis of Gene Signaling Networks , 2007, CIARP.

[21]  F. Wilcoxon Individual Comparisons by Ranking Methods , 1945 .

[22]  Andrew Pekosz,et al.  The Xs and Y of immune responses to viral vaccines. , 2010, The Lancet. Infectious diseases.

[23]  L. Carin,et al.  A Host Transcriptional Signature for Presymptomatic Detection of Infection in Humans Exposed to Influenza H1N1 or H3N2 , 2013, PloS one.

[24]  J. Banchereau,et al.  Whole Blood Gene Expression Profiles to Assess Pathogenesis and Disease Severity in Infants with Respiratory Syncytial Virus Infection , 2013, PLoS medicine.

[25]  J. Rello,et al.  Pandemic Influenza , 2018, Emergency Medicine.

[26]  D. Wilkinson Gene Expression Patterns , 2002, Brain Research.

[27]  S. Crosby,et al.  Gene expression profiles in febrile children with defined viral and bacterial infection , 2013, Proceedings of the National Academy of Sciences.

[28]  Alexander A. Morgan,et al.  A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation , 2013, The Journal of experimental medicine.

[29]  Colin G Fink,et al.  Transcriptomic Profiling in Childhood H1N1/09 Influenza Reveals Reduced Expression of Protein Synthesis Genes , 2013, The Journal of infectious diseases.

[30]  Yuri Kotliarov,et al.  Global Analyses of Human Immune Variation Reveal Baseline Predictors of Postvaccination Responses , 2014, Cell.

[31]  N. Hacohen,et al.  A Physical and Regulatory Map of Host-Influenza Interactions Reveals Pathways in H1N1 Infection , 2009, Cell.

[32]  Purvesh Khatri,et al.  Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases , 2014, Acta neuropathologica communications.

[33]  Stephen Huang,et al.  Aberrant Cell Cycle and Apoptotic Changes Characterise Severe Influenza A Infection – A Meta-Analysis of Genomic Signatures in Circulating Leukocytes , 2011, PloS one.

[34]  A. Butte,et al.  SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer , 2014, Nature.

[35]  Mark M. Davis,et al.  Apoptosis and other immune biomarkers predict influenza vaccine responsiveness , 2013, Molecular systems biology.

[36]  V. Fraser,et al.  Case-Control Study of Clinical Features of Influenza in Hospitalized Patients , 2008, Infection Control & Hospital Epidemiology.

[37]  Jean H. Chang,et al.  Host Regulatory Network Response to Infection with Highly Pathogenic H5N1 Avian Influenza Virus , 2011, Journal of Virology.

[38]  D. Rawlings,et al.  CD38 Signaling Regulates B Lymphocyte Activation via a Phospholipase C (PLC)-γ2-Independent, Protein Kinase C, Phosphatidylcholine-PLC, and Phospholipase D-Dependent Signaling Cascade1 , 2005, The Journal of Immunology.

[39]  Eva K. Lee,et al.  Systems Biology of Seasonal Influenza Vaccination in Humans , 2011, Nature Immunology.

[40]  Pooja Mittal,et al.  A novel signaling pathway impact analysis , 2009, Bioinform..

[41]  R. Fisher,et al.  Statistical Methods for Research Workers , 1930, Nature.

[42]  Terri Wrin,et al.  The prevalence of antiretroviral drug resistance in the United States , 2004, AIDS.

[43]  Douglas G Altman,et al.  Key Issues in Conducting a Meta-Analysis of Gene Expression Microarray Datasets , 2008, PLoS medicine.

[44]  M. Ison,et al.  Influenza 2010–2011: Lessons from the 2009 pandemic , 2010, Cleveland Clinic Journal of Medicine.

[45]  Stephen J. Huang,et al.  A distinct influenza infection signature in the blood transcriptome of patients with severe community-acquired pneumonia , 2012, Critical Care.

[46]  Frank Wilcoxon,et al.  Probability tables for individual comparisons by ranking methods. , 1947 .

[47]  Purvesh Khatri,et al.  A comprehensive time-course–based multicohort analysis of sepsis and sterile inflammation reveals a robust diagnostic gene set , 2015, Science Translational Medicine.