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

Laia Alsina, Elisabeth Israelsson, Matthew C. Altman, Kristen K. Dang, Pegah Ghandil, Laura Israel, Horst Von Bernuth, Nicole Baldwin, Huanying Qin, Zongbo Jin, Romain Banchereau, Esperanza Anguiano, Alexei Ionan, Laurent Abel, Anne Puel, Capucine Picard, Virginia Pascual, Jean Laurent Casanova, Damien J. Chaussabel

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29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1134-1142
Number of pages9
JournalNature Immunology
Volume15
Issue number12
DOIs
Publication statusPublished - 18 Nov 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

Cite this

Alsina, L., Israelsson, E., Altman, M. C., Dang, K. K., Ghandil, P., Israel, L., Von Bernuth, H., Baldwin, N., Qin, H., Jin, Z., Banchereau, R., Anguiano, E., Ionan, A., Abel, L., Puel, A., Picard, C., Pascual, V., Casanova, J. L., & Chaussabel, D. J. (2014). A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4. Nature Immunology, 15(12), 1134-1142. https://doi.org/10.1038/ni.3028