Cellular metabolism constrains innate immune responses in early human ontogeny

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.

Prenatal inflammation suppresses blood Th1 polarization and gene clusters related to cellular energy metabolism in preterm newborns

“…46 Different from myeloid cells, T cell activation and polarization also require increased oxidative phosphorylation to obtain a vast energy demand 47,48 and in our study, the impaired oxidative phosphorylation and ribosomal activity in LPS pigs support well the trend of suppressed Th1 polarization. The increased immune suppression and reduced metabolic activities in LPS vs CON pigs are also similar to that observed in preterm vs term monocytes, 5 and in septic conditions. 8,42 This cellular programming pattern may reflect even a higher degree of disease tolerance strategy than that in preterm animals without prenatal insults, to avoid highly energy-consuming inflammatory responses following pathogenic encounters.…”

“…Reduced ribosomal activity may inhibit the translation of important genes related to immune responses and Th1 polarization, while decreased oxidative phosphorylation is associated with reduced ATP synthesis as well as a metabolically quiescent state. 5 Mitochondrial oxidative phosphorylation is also vital during acute inflammation 42 and decreased ATP production is related to more severe systemic inflammation and poorer septic outcomes and survival rate. [43][44][45] Reduced ribosomal activities may also be the consequences of reduced oxidative phosphorylation and ATP synthesis because protein synthesis via ribosomal activity is among the most energy-consuming processes.…”

“…3,4 This serves to minimize the immunopathology of energetically costly inflammatory responses and instead to use energy for maintenance of organ functions. 5 These phenomena explain the inverse correlation between the frequency of blood regulatory T cells (Treg) and gestational age in noninfected preterm infants, and higher blood Treg frequencies in preterm than term infants. 6,7 The disease tolerance strategy makes infants, especially preterm infants, withstand 10-100 times greater levels of circulating bacteria, relative to adults.…”

BCG as a Case Study for Precision Vaccine Development: Lessons From Vaccine Heterogeneity, Trained Immunity, and Immune Ontogeny

“…Examples include: (a) cholesterol, which participates in cell membrane remodeling and increased sensitivity to subsequent stimuli, (b) succinate and fumarate, which antagonize histone demethylation and suppress antiinflammatory genes, (c) acetyl-CoA, an essential substrate for acetylating processes, and (d) NAD + which is important for epigenetic changes resulting in a switch from glucose to fatty acid oxidation during LPS-induced tolerance and sepsis-induced immune paralysis (Conti et al, 2019). Immunometabolic changes may be different between newborns and adults, reflecting the differential nutritional and metabolic needs of the two groups, as well as their distinct immune response to pathogens (Kan et al, 2018;Dreschers et al, 2019). Indeed the ontogeny of immunometabolism is an emerging and promising area of research (Conti et al, 2019) (see Box 2).…”

Commentary: Is the developmentally immature immune response in paediatric sepsis a recapitulation of immune tolerance?

“…However, we currently lack direct experimental evidence from clinical studies and relevant genomic analyses that can establish these distinctively altered immune responses during sepsis and associate these features with the age-related maturational states of the immune system (18,19). Critical understanding of these immune and immunoregulatory functions through the prenatal, neonatal, and postnatal developmental stages have to be evaluated from the overall evolutionarily governing principles that are related to entropy; i.e., the metabolic programming during fetal development is tuned toward conservation of energy, and these aspects characteristically correlate with the immune responses that are resistant or homeostatic vs. responsive or tolerogenic (20,21). These aspects have profound clinical implications as we routinely encounter altered physiological states during pediatric vaccinations when the host immune response is primed through vaccine adjuncts.…”