Cellular metabolism constrains innate immune responses in early human ontogeny

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. Mirmira, Colin J. Ross, Dan S. Luciani, Eric Jan and Pascal M. Lavoie ()
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Bernard Kan: BC Children’s Hospital Research Institute
Christina Michalski: BC Children’s Hospital Research Institute
Helen Fu: BC Children’s Hospital Research Institute
Hilda H. T. Au: Life Sciences Institute, University of British Columbia
Kelsey Lee: BC Children’s Hospital Research Institute
Elizabeth A. Marchant: BC Children’s Hospital Research Institute
Maye F. Cheng: BC Children’s Hospital Research Institute
Emily Anderson-Baucum: Indiana University School of Medicine
Michal Aharoni-Simon: BC Children’s Hospital Research Institute
Peter Tilley: BC Children’s and Women’s Hospitals
Raghavendra G. Mirmira: Indiana University School of Medicine
Colin J. Ross: BC Children’s Hospital Research Institute
Dan S. Luciani: BC Children’s Hospital Research Institute
Eric Jan: Life Sciences Institute, University of British Columbia
Pascal M. Lavoie: BC Children’s Hospital Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07215-9

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