A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4

Nat Immunol. 2014 Dec;15(12):1134-42. doi: 10.1038/ni.3028. Epub 2014 Oct 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Cluster Analysis
  • Female
  • Gene Expression Profiling
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology*
  • Infant
  • Interleukin-1 Receptor-Associated Kinases / genetics*
  • Interleukin-1 Receptor-Associated Kinases / immunology
  • Male
  • Mutation*
  • Myeloid Differentiation Factor 88 / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Primary Immunodeficiency Diseases
  • Transcriptome


  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases

Supplementary concepts

  • IRAK4 Deficiency
  • MYD88 Deficiency

Associated data

  • GEO/GSE25742