Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia

&NA; Rationale: Heterogeneity in the septic response has hindered efforts to understand pathophysiology and develop targeted therapies. Source of infection, with different causative organisms and temporal changes, might influence this heterogeneity. Objectives: To investigate individual and temporal variations in the transcriptomic response to sepsis due to fecal peritonitis, and to compare these with the same parameters in community‐acquired pneumonia. Methods: We performed genome‐wide gene expression profiling in peripheral blood leukocytes of adult patients admitted to intensive care with sepsis due to fecal peritonitis (n = 117) or community‐acquired pneumonia (n = 126), and of control subjects without sepsis (n = 10). Measurements and Main Results: A substantial portion of the transcribed genome (18%) was differentially expressed compared with that of control subjects, independent of source of infection, with eukaryotic initiation factor 2 signaling being the most enriched canonical pathway. We identified two sepsis response signature (SRS) subgroups in fecal peritonitis associated with early mortality (P = 0.01; hazard ratio, 4.78). We defined gene sets predictive of SRS group, and serial sampling demonstrated that subgroup membership is dynamic during intensive care unit admission. We found that SRS is the major predictor of transcriptomic variation; a small number of genes (n = 263) were differentially regulated according to the source of infection, enriched for IFN signaling and antigen presentation. We define temporal changes in gene expression from disease onset involving phagosome formation as well as natural killer cell and IL‐3 signaling. Conclusions: The majority of the sepsis transcriptomic response is independent of the source of infection and includes signatures reflecting immune response state and prognosis. A modest number of genes show evidence of specificity. Our findings highlight opportunities for patient stratification and precision medicine in sepsis.

[1]  Jordi Rello,et al.  International study of the prevalence and outcomes of infection in intensive care units. , 2009, JAMA.

[2]  R. Hotchkiss,et al.  Immunosuppression in Patients Who Die of Sepsis and Multiple Organ Failure , 2012 .

[3]  Stephen J. Huang,et al.  Gene-expression profiling of Gram-positive and Gram-negative sepsis in critically ill patients* , 2008, Critical care medicine.

[4]  Jianwei Wang,et al.  Lysosome-associated membrane glycoprotein 3 is involved in influenza A virus replication in human lung epithelial (A549) cells , 2011, Virology Journal.

[5]  M. Paye,et al.  Early and dynamic changes in gene expression in septic shock patients: a genome-wide approach , 2014, Intensive Care Medicine Experimental.

[6]  J. Oosterheert,et al.  Immunomodulatory effects of macrolides during community-acquired pneumonia: a literature review. , 2012, The Journal of antimicrobial chemotherapy.

[7]  Olga M. Pena,et al.  Endotoxin Tolerance Represents a Distinctive State of Alternative Polarization (M2) in Human Mononuclear Cells , 2011, The Journal of Immunology.

[8]  S. Opal,et al.  Sepsis: a roadmap for future research. , 2015, The Lancet. Infectious diseases.

[9]  H. Blau,et al.  Anti-Inflammatory Effects of Moxifloxacin on Activated Human Monocytic Cells: Inhibition of NF-κB and Mitogen-Activated Protein Kinase Activation and of Synthesis of Proinflammatory Cytokines , 2004, Antimicrobial Agents and Chemotherapy.

[10]  A. Zwinderman,et al.  A molecular biomarker to diagnose community-acquired pneumonia on intensive care unit admission. , 2015, American journal of respiratory and critical care medicine.

[11]  Terence P. Speed,et al.  On Gene Ranking Using Replicated Microarray Time Course Data , 2009, Biometrics.

[12]  B. Finlay,et al.  Invasive and adherent bacterial pathogens co-Opt host clathrin for infection. , 2008, Nature Reviews Microbiology.

[13]  Gilles Clermont,et al.  Severe community-acquired pneumonia: use of intensive care services and evaluation of American and British Thoracic Society Diagnostic criteria. , 2002, American journal of respiratory and critical care medicine.

[14]  S. Schmid,et al.  Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis , 2002, The Journal of cell biology.

[15]  J. Vincent,et al.  Infection in Intensive Care Units International Study of the Prevalence and Outcomes of , 2009 .

[16]  Robert J Freishtat,et al.  BMC Medicine BioMed Central , 2009 .

[17]  G. Clarke,et al.  Patients with faecal peritonitis admitted to European intensive care units: an epidemiological survey of the GenOSept cohort , 2014, Intensive Care Medicine.

[18]  J. Carcillo,et al.  Differences between adult and pediatric septic shock. , 2011, Minerva anestesiologica.

[19]  Jeremy J. W. Chen,et al.  Differential gene expression in gram-negative and gram-positive sepsis. , 2004, American journal of respiratory and critical care medicine.

[20]  J. Marshall.  Why have clinical trials in sepsis failed? , 2014, Trends in molecular medicine.

[21]  R. Hotchkiss,et al.  Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy , 2013, Nature Reviews Immunology.

[22]  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.

[23]  Adil Rafiq Rather,et al.  The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) , 2015 .

[24]  G. Clarke,et al.  Patients with community acquired pneumonia admitted to European intensive care units: an epidemiological survey of the GenOSept cohort , 2014, Critical Care.

[25]  Peter J Munson,et al.  Gene expression profiles of peripheral blood leukocytes after endotoxin challenge in humans. , 2006, Physiological genomics.

[26]  C. Edmiston,et al.  Surgical sepsis: constancy of antibiotic susceptibility of causative organisms. , 1995, Surgery.

[27]  C. Lindsell,et al.  Developing a clinically feasible personalized medicine approach to pediatric septic shock. , 2015, American journal of respiratory and critical care medicine.

[28]  Evan Z. Macosko,et al.  Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets , 2015, Cell.

[29]  P. Khatri,et al.  Robust classification of bacterial and viral infections via integrated host gene expression diagnostics , 2016, Science Translational Medicine.

[30]  T. Kajiji,et al.  Potent Phagocytic Activity with Impaired Antigen Presentation Identifying Lipopolysaccharide-Tolerant Human Monocytes: Demonstration in Isolated Monocytes from Cystic Fibrosis Patients1 , 2009, The Journal of Immunology.

[31]  H. Wong,et al.  Gene expression profiling in sepsis: timing, tissue, and translational considerations. , 2014, Trends in molecular medicine.

[32]  Anna Rautanen,et al.  Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study , 2016, The Lancet. Respiratory medicine.

[33]  H. Baker,et al.  Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis. , 2016, Physiological genomics.

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

[35]  H. Wong,et al.  Pediatric Sepsis - Part I: "Children are not small adults!" , 2011, The open inflammation journal.

[36]  K. A. Fields,et al.  Eukaryotic Initiation Factor 2 (eIF2) Signaling Regulates Proinflammatory Cytokine Expression and Bacterial Invasion* , 2012, The Journal of Biological Chemistry.

[37]  Jason Phua,et al.  Characteristics and outcomes of culture-negative versus culture-positive severe sepsis , 2013, Critical Care.

[38]  P. Marik.  The clinical features of severe community-acquired pneumonia presenting as septic shock. Norasept II Study Investigators. , 2000, Journal of critical care.

[39]  John D. Storey,et al.  A genomic storm in critically injured humans , 2011, The Journal of experimental medicine.

[40]  M. Billingsley,et al.  Functional and structural properties of stannin: Roles in cellular growth, selective toxicity, and mitochondrial responses to injury , 2006, Journal of cellular biochemistry.

[41]  Adam Linder,et al.  An Endotoxin Tolerance Signature Predicts Sepsis and Organ Dysfunction at Initial Clinical Presentation , 2014, EBioMedicine.

[42]  Martin Vingron,et al.  Variance stabilization applied to microarray data calibration and to the quantification of differential expression , 2002, ISMB.

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

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

[45]  H. Baker,et al.  Molecular Characterization of the Acute Inflammatory Response to Infections with Gram-Negative versus Gram-Positive Bacteria , 2003, Infection and Immunity.

[46]  P. Brown,et al.  Gene expression patterns in human placenta. , 2006, Proceedings of the National Academy of Sciences of the United States of America.