Energy Demands of Early Life Drive a Disease Tolerant Phenotype and Dictate Outcome in Neonatal Bacterial Sepsis

Bacterial sepsis is one of the leading causes of death in newborns. In the face of growing antibiotic resistance, it is crucial to understand the pathology behind the disease in order to develop effective interventions. Neonatal susceptibility to sepsis can no longer be attributed to simple immune immaturity in the face of mounting evidence that the neonatal immune system is tightly regulated and well controlled. The neonatal immune response is consistent with a “disease tolerance” defense strategy (minimizing harm from immunopathology) whereas adults tend toward a “disease resistance” strategy (minimizing harm from pathogens). One major advantage of disease tolerance is that is less energetically demanding than disease resistance, consistent with the energetic limitations of early life. Immune effector cells enacting disease resistance responses switch to aerobic glycolysis upon TLR stimulation and require steady glycolytic flux to maintain the inflammatory phenotype. Rapid and intense upregulation of glucose uptake by immune cells necessitates an increased reliance on fatty acid metabolism to (a) fuel vital tissue function and (b) produce immunoregulatory intermediates which help control the magnitude of inflammation. Increasing disease resistance requires more energy: while adults have fat and protein stores to catabolize, neonates must reallocate resources away from critical growth and development. This understanding of sepsis pathology helps to explain many of the differences between neonatal and adult immune responses. Taking into account the central role of metabolism in the host response to infection and the severe metabolic demands of early life, it emerges that the striking clinical susceptibility to bacterial infection of the newborn is at its core a problem of metabolism. The evidence supporting this novel hypothesis, which has profound implications for interventions, is presented in this review.