How the human immune system responds to infection in early is poorly understood. This talk will discuss how systems pathway biology approaches have helped reveal an altered immune homeostatic set-point in early life bacterial infections that exacerbates myeloid regulatory signalling and sugar-lipid metabolism with a concomitant inhibition of lymphoid responses. Innate immune-negative feedback opposes innate immune activation while suppression of T-cell co-stimulation is coincident with selective upregulation of a highly focused set of co-inhibitory pathways. These regulatory changes determine the set-point for immune homeostasis upon infection. Notably by integrating specific immune and metabolic pathways inter-patient heterogeneity can be overcome and the inference of a novel immune-metabolic axis accurately predicts sepsis in neonates and infants. These findings lay the foundation for future translation of host pathways in advancing diagnostic, prognostic and therapeutic strategies for neonatal sepsis.