Modifiable Determinants of Mortality in Neonatal Sepsis

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PROJECT SUMMARY Neonatal sepsis is one of the most difficult and costly problems to treat and prevent. Despite antimicrobial therapy, 39% of neonates with sepsis die or suffer major chronic morbidity. Although sepsis mortality and morbidity is bimodal, with peaks at the extremes of age (very old and very young), investigations of the neonatal-host immune response to sepsis and the mechanisms behind poor long-term outcomes have lagged behind older children and adults. Preterm neonates differ from more mature populations in terms of their baseline immune status. For example, healthy, uninfected human neonates have elevated levels of circulating IL-18 when compared to adults and exhibit increased IL-18 production with infection. Recently, we showed that IL-18 deletion protected neonates from sepsis mortality and conversely, exposure to IL-18 to mimic the human preterm condition resulted in gut injury, enhanced systemic inflammation, increased bacteremia and mortality in murine neonates with sepsis. Following IL-18 exposure in septic mice, IL-17A transcript was elevated early and exclusively in the gut and lung, and plasma IL-17A protein was 140-fold greater than levels in septic mice without IL-18 exposure. We described a novel deleterious inflammatory signaling pathway in the preterm infant led by IL-18, dependent upon IL-1R1 signaling, and culminating in excessive IL-17A production by γδT cells that was mechanistically responsible for mortality. We also demonstrated that we could reverse IL-18- enhanced sepsis mortality via pharmacologic IL-17 receptor (IL-17R) blockade. We now show this treatment is associated with a reduction in acute lung injury (ALI), the penultimate pathway to death in human neonates. The studies proposed in this application are prerequisite to therapeutic trials and will test the hypotheses that IL-1α is the primary ligand that leads to mortality and deleterious IL-17A production in the gut while IL-1β is the primary ligand for IL-17A production in the lung (Aim 1), that IL-1R1-dependent IL-17A production by γδT cells in both the gut and the lung is augmented by IL-23 (Aim 2), and ALI is a principal and preventable mechanism for death in neonates with sepsis and is secondary to primary gut injury (Aim 3). First, we will determine the IL- 1R1 ligand(s) responsible for mortality and the production of IL-17A in the gut and lung during neonatal sepsis (Aim 1). Second, we will identify whether there is an additional absolute requirement of IL-23 for IL-17A production by γδT cells downstream from IL-1R1 signaling in the gut and in the lung (Aim 2). Finally, we will resolve whether IL-17A is an ideal therapeutic target to protect neonatal mice from sepsis-induced acute lung injury (Aim 3). Cumulatively, we will search for hitherto unknown contributors and regulators of this unique pathway and thus generate new knowledge about the poorly understood parameters of neonatal sepsis through determination of the role of IL-18/IL-1/IL-17A signaling in sepsis-induced organ injury.