Graduate Student West Virginia Univ. Morgantown, West Virginia, United States
Disclosure(s):
Melina Joshi, MA: No financial relationships to disclose
Introduction/Rationale: Human newborns exhibit increased risk of bacterial sepsis. Interleukin (IL)–27, an immune-suppressive cytokine has been found to be elevated in neonatal human cells and mice. Prior work from our lab has demonstrated that IL-27 is detrimental to neonatal mice during gram-negative sepsis. In the present work, we aimed to understand the role of IL-27 in a gram-positive neonatal sepsis model with a focus on S. agalactiae (GBS), a leading cause of neonatal sepsis.
Methods: Neonatal C57BL/6 (WT) and IL-27 receptor-deficient (IL-27Rα-/-) mice were subcutaneously infected with GBS on day 4 of life. Morbidity and mortality were evaluated over 7 days. This included tissue-specific measurements of inflammatory markers and bacterial burdens. In addition, bone marrow-derived macrophages (BMDMs) from WT and IL-27Rα-/- neonatal mice were infected with GBS in vitro to evaluate bacterial clearance.
Results: Mice deficient in IL-27 signaling exhibited improved survival, weight gain, and maintenance of blood glucose levels following GBS infection compared to WT littermates. These aligned with reduced bacterial burdens in blood and peripheral tissues of IL-27Rα-/- pups. In response to GBS infection, WT pups displayed a tissue-specific increase in IL-27 gene expression. Furthermore, IL-27Rα-/- BMDMs demonstrated more efficient clearance of GBS than WT BMDMs in vitro. While IL-27 is known to be associated with suppressed inflammation, IL-27 signaling was associated with an increased inflammatory cytokine response during neonatal sepsis. In contrast to our prior E. coli model, was a slower progression of disease with a critical window for morbidity and mortality occurring at 48-72 h post-infection.
Conclusion: Our findings reveal that IL-27 signaling correlates with increased morbidity and mortality in GBS-infected neonatal mice. This suggests that IL-27 compromises the host response during neonatal GBS sepsis and may represent a target for therapeutic interventions.
