Regulation of host metabolism and defense strategies to survive neonatal infection

Two distinct defense strategies, resistance and tolerance, enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on tolerance to cope with infection. However, this approach may fail as pathogen levels surpass a critical threshold, prompting a shift to resistance that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between tolerance and resistance in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non- survivors in Staphylococcus epidermidis ( S. epidermidis )-infected preterm piglets, mimicking infection in preterm infants. Relative to non-survivors, survivors displayed elevated resistance during the early phase of infection, followed by stronger tolerance in later stages. Conversely, animals succumbing to sepsis showed clear signs of respiratory and metabolic acidosis, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the tolerance phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics supported the finding of enhanced mitochondrial metabolism in survivors. Our findings suggest a link between mitochondrial metabolism, disease tolerance, and ultimately improved survival during infections in newborns. Metabolic regulations related to tolerance may be exploited to discover novel therapeutics for neonatal infection.