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Cellular metabolism constrains innate immune responses in early human ontogeny

Author

Listed:
  • Bernard Kan

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Christina Michalski

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Helen Fu

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Hilda H. T. Au

    (Life Sciences Institute, University of British Columbia)

  • Kelsey Lee

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Elizabeth A. Marchant

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Maye F. Cheng

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Emily Anderson-Baucum

    (Indiana University School of Medicine)

  • Michal Aharoni-Simon

    (BC Children’s Hospital Research Institute
    Kaplan Medical Center)

  • Peter Tilley

    (BC Children’s and Women’s Hospitals
    University of British Columbia)

  • Raghavendra G. Mirmira

    (Indiana University School of Medicine)

  • Colin J. Ross

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Dan S. Luciani

    (BC Children’s Hospital Research Institute
    University of British Columbia)

  • Eric Jan

    (Life Sciences Institute, University of British Columbia)

  • Pascal M. Lavoie

    (BC Children’s Hospital Research Institute
    University of British Columbia)

Abstract

Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny.

Suggested Citation

  • Bernard Kan & Christina Michalski & Helen Fu & Hilda H. T. Au & Kelsey Lee & Elizabeth A. Marchant & Maye F. Cheng & Emily Anderson-Baucum & Michal Aharoni-Simon & Peter Tilley & Raghavendra G. Mirmir, 2018. "Cellular metabolism constrains innate immune responses in early human ontogeny," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07215-9
    DOI: 10.1038/s41467-018-07215-9
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