Cellular metabolism constrains innate immune responses in early human ontogeny.

TitleCellular metabolism constrains innate immune responses in early human ontogeny.
Publication TypeJournal Article
Year of Publication2018
AuthorsKan B, Michalski C, Fu H, Au HHT, Lee K, Marchant EA, Cheng MF, Anderson-Baucum E, Aharoni-Simon M, Tilley P, Mirmira RG, Ross CJ, Luciani DS, Jan E, Lavoie PM
JournalNat Commun
Volume9
Issue1
Pagination4822
Date Published11/2018
ISSN2041-1723
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.

DOI10.1038/s41467-018-07215-9
Alternate JournalNat Commun
PubMed ID30446641
PubMed Central IDPMC6240060