title: A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4.
abstract: Loss of function of the kinase IRAK4 or the adaptor MyD88 in humans interrupts a pathway critical for pathogen sensing and ignition of inflammation. However, patients with loss-of-function mutations in the genes encoding these factors are, unexpectedly, susceptible to only a limited range of pathogens. We employed a systems approach to investigate transcriptome responses following in vitro exposure of patients' blood to agonists of Toll-like receptors (TLRs) and receptors for interleukin 1 (IL-1Rs) and to whole pathogens. Responses to purified agonists were globally abolished, but variable residual responses were present following exposure to whole pathogens. Further delineation of the latter responses identified a narrow repertoire of transcriptional programs affected by loss of MyD88 function or IRAK4 function. Our work introduces the use of a systems approach for the global assessment of innate immune responses and the characterization of human primary immunodeficiencies.
authors.affiliation: 1] Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA. [2] Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona Universitat de Barcelona, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Alsina
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Israelsson
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Altman
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
authors.forename: Kristen K
authors.initials: KK
authors.lastname: Dang
authors.affiliation: 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France.
authors.forename: Pegah
authors.initials: P
authors.lastname: Ghandil
authors.affiliation: 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Israel
authors.affiliation: 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France. [3] Department of Pediatric Pneumology and Immunology, Charité Hospital-Humboldt University, Berlin, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: von Bernuth
authors.affiliation: Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Baldwin
authors.affiliation: Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA.
authors.forename: Huanying
authors.initials: H
authors.lastname: Qin
authors.affiliation: Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA.
authors.forename: Zongbo
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA.
authors.forename: Romain
authors.initials: R
authors.lastname: Banchereau
authors.affiliation: Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Anguiano
authors.affiliation: Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Ionan
authors.affiliation: 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.affiliation: 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France. [3] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.affiliation: 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France. [3] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA. [4] Study Center of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital, Paris, France. [5] Howard Hughes Medical Institute, New York, USA.
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.affiliation: Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
authors.affiliation: 1] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, IMAGINE Institute, Paris, France. [2] Paris Descartes University, Paris, France. [3] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA. [4] Howard Hughes Medical Institute, New York, USA. [5] Pediatric Hematology-Immunology Unit, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jean Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: 1] Baylor Institute for Immunology Research and Baylor Research Institute, Dallas, Texas, USA. [2] Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA. [3] Sidra Medical and Research Center, Doha, Qatar.
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology*; D007223:Infant; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000276:immunology; D008297:Male; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D000081207:Primary Immunodeficiency Diseases; D059467:Transcriptome
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases