title: Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses.
abstract: Systems approaches for the study of immune signaling pathways have been traditionally based on purified cells or cultured lines. However, in vivo responses involve the coordinated action of multiple cell types, which interact to establish an inflammatory microenvironment. We employed standardized whole-blood stimulation systems to test the hypothesis that responses to Toll-like receptor ligands or whole microbes can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, that captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. Furthermore, we used donor variability to identify shared inter-cellular pathways and trace cytokine loops involved in gene expression. This provides strategies for dimension reduction of large datasets and deconvolution of innate immune responses applicable for characterizing immunomodulatory molecules. Moreover, we provide an interactive R-Shiny application with healthy donor reference values for induced inflammatory genes.
authors: Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, Paris 75015, France; INSERM U1223, Paris 75015, France; Department of Cancer Immunology, Genentech Inc., San Francisco, CA 94080, USA.
authors: Alejandra
authors: A
authors: Urrutia
authors: Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, Paris 75015, France; INSERM U1223, Paris 75015, France; Center for Translational Research, Institut Pasteur, Paris 75015, France.
authors: Darragh
authors: D
authors: Duffy
authors: Center for Translational Research, Institut Pasteur, Paris 75015, France.
authors: Vincent
authors: V
authors: Rouilly
authors: Center for Translational Research, Institut Pasteur, Paris 75015, France.
authors: Céline
authors: C
authors: Posseme
authors: Center for Translational Research, Institut Pasteur, Paris 75015, France.
authors: Raouf
authors: R
authors: Djebali
authors: Center for Translational Research, Institut Pasteur, Paris 75015, France; IGDA, Institut Pasteur, Paris 75015, France; Centro de Matemática, Facultad de Ciencias, Universidad de la República, 11200 Montevideo, Uruguay.
authors: Gabriel
authors: G
authors: Illanes
authors: Center for Translational Research, Institut Pasteur, Paris 75015, France.
authors: Valentina
authors: V
authors: Libri
authors: Institut Curie, Centre de Recherche, Département de recherche translationnelle, Plateforme de Génomique, Paris 75005, France.
authors: Benoit
authors: B
authors: Albaud
authors: Institut Curie, Centre de Recherche, Département de recherche translationnelle, Plateforme de Génomique, Paris 75005, France.
authors: David
authors: D
authors: Gentien
authors: Center for Translational Research, Institut Pasteur, Paris 75015, France.
authors: Barbara
authors: B
authors: Piasecka
authors: Center for Translational Research, Institut Pasteur, Paris 75015, France.
authors: Milena
authors: M
authors: Hasan
authors: IGDA, Institut Pasteur, Paris 75015, France; Centre for Mathematical Sciences, Lund University, 221 00 Lund, Sweden.
authors: Magnus
authors: M
authors: Fontes
authors: Laboratory of Human Evolutionary Genetics, Department of Genomes and Genetics, Institut Pasteur, Paris 75015, France; CNRS URA3012, Paris 75015, France. Electronic address: quintana@pasteur.fr.
authors: Lluis
authors: L
authors: Quintana-Murci
authors: Laboratory of Dendritic Cell Immunobiology, Department of Immunology, Institut Pasteur, Paris 75015, France; INSERM U1223, Paris 75015, France; Center for Translational Research, Institut Pasteur, Paris 75015, France; Department of Cancer Immunology, Genentech Inc., San Francisco, CA 94080, USA. Electronic address: albertm@pasteur.fr.
authors: Matthew L
authors: ML
authors: Albert
mesh_terms: D000328:Adult; D001419:Bacteria / Q000378:metabolism; D001769:Blood / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000235:genetics*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016207:Cytokines; D051193:Toll-Like Receptors