# Modifiable Determinants of Mortality in Neonatal Sepsis

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $381,250

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10166871
- **Project number:** 5R01GM128452-04
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** James Lawrence Wynn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166871

## Citation

> US National Institutes of Health, RePORTER application 10166871, Modifiable Determinants of Mortality in Neonatal Sepsis (5R01GM128452-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10166871. Licensed CC0.

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