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 ??T 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-1? is the primary ligand that leads to mortality and deleterious IL-17A production in the gut while IL-1? is the primary ligand for IL-17A production in the lung (Aim 1), that IL-1R1-dependent IL-17A production by ??T 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 ??T 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.

Public Health Relevance

Newborns, particularly those born prematurely, have a substantial risk of sepsis-related death or life-long survivor morbidity. In this proposal, we examine a new pathway that leads to organ injury in neonatal sepsis observed in two distinct organ systems (the lung and gut), and identify both the responsible cell populations and the local mediators that regulate this tissue injury. These studies will provide a strong theoretical foundation for novel clinical interventions in neonatal sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM128452-02
Application #
9696865
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dunsmore, Sarah
Project Start
2018-06-01
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Florida
Department
Pediatrics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Benjamin, John T; Moore, Daniel J; Bennett, Clayton et al. (2018) Cutting Edge: IL-1? and Not IL-1? Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality. J Immunol 201:2873-2878
Lawrence, Shelley M; Ruoss, Jessica Lauren; Wynn, James L (2018) IL-17 in neonatal health and disease. Am J Reprod Immunol 79:e12800
Lawrence, Shelley M; Wynn, James L (2018) Chorioamnionitis, IL-17A, and fetal origins of neurologic disease. Am J Reprod Immunol 79:e12803
Collins, Amélie; Weitkamp, Jörn-Hendrik; Wynn, James L (2018) Why are preterm newborns at increased risk of infection? Arch Dis Child Fetal Neonatal Ed 103:F391-F394