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

Abstract

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.

Keywords: disease tolerance; infection; inflammation; metabolism; neonate; sepsis.

Figure 1

Resource allocation in bacterial sepsis explains the need for disease tolerance as a defense strategy in neonates. Bacterial infection requires a massive, sustained energy input in order to mount an inflammatory, disease resistance response. (A) Adults have substantial energy stores and a resting metabolic rate that is not near its max capacity, which allows for a burst of energy to be rapidly allocated toward fighting the infection. If the infection results in a prolonged state of sepsis, eventually the amount of energy required to maintain the inflammatory response necessitates a siphoning from other vital functions. Too much energy siphoned can result in organ failure and lead to mortality. (B) Neonates have much higher basal metabolic needs, lower energy stores than adults, and are unable to increase resting energy expenditure during infection. Allocating resources toward fighting infection therefore comes at a greater cost to neonates, which has resulted in an increased reliance on disease tolerance as a defense strategy. Mortality due to sepsis may be a result of the energetic demands of a sustained response, rather than a direct result uncontrolled inflammation.