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Published on: November 3, 2014
Cellular metabolism constrains innate immune responses in early human ontogeny
Bernard Kan1,2, Christina Michalski1,2, Helen Fu1,2
1BC Children's Hospital Research Institute, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
Insights
Infants born prematurely have immature immune cells with metabolic and ribosomal defects, hindering responses to pathogens like Candida. This immaturity is linked to developmental programming to conserve energy.
Area of Science:
- Immunology
- Developmental Biology
- Metabolic Pathways
Background:
- Fetal and infant immune responses are significantly weaker than adult responses.
- The underlying molecular and metabolic mechanisms of this immune developmental immaturity are not well understood.
Purpose of the Study:
- To investigate the molecular and metabolic basis for the attenuated immune responses observed in monocytes from preterm infants.
Main Methods:
- Transcriptomic profiling
- Metabolic profiling
- Polysome profiling
- Monocyte isolation from preterm infants
Main Results:
- Monocytes from preterm infants show impaired PPAR-γ (peroxisome proliferator-activated receptor gamma) regulated metabolic pathways.
- Limited glycolytic capacity and reduced ribosomal activity were observed, impacting cytokine and MALT1 (Mucosa-Associated Lymphoid Tissue 1) signalosome gene translation.
- Essential phagocytosis functions remained largely unaffected.
- mTOR (mechanistic target of rapamycin) and DNA Damage Inducible Transcript 4-Like (DDIT4L) were implicated in regulating these metabolic constraints.
Conclusions:
- The study identifies specific metabolic and translational defects in preterm infant monocytes, explaining their susceptibility to pathogens.
- These findings suggest the fetal immune system is programmed to limit energetically expensive immune responses during development.
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.
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