Targeting iron to improve outcomes in neonatal Escherichia coli sepsis

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Infection is the leading cause of mortality during the neonatal period. Early onset sepsis (EOS), which occurs within the first 3-5 days after birth, has a mortality rate of approximately 25%. Escherichia coli (E. coli) is one of the leading causes of EOS in both term and preterm infants. Prompt initiation of antibiotics is crucial to survival in EOS, but is challenging because EOS presents with nonspecific signs and symptoms without reliable biomarkers to aid in diagnosis. Empiric antibiotic therapy for all critically ill neonates is problematic because unnecessary antibiotic exposure is associated with numerous short and long-term morbidities, including necrotizing enterocolitis, sepsis beyond the first five days of life and persistent wheezing and asthma during childhood. This highlights the need to identify additional therapies to treat EOS. Historically, neonatal susceptibility to infection has been attributed to developmental “immaturity” of the immune system. However, more recent work suggests that neonatal innate immune cells can mount robust and effective immune responses in many contexts. This points to the need for more research into immune cell independent defects that may contribute to neonatal infection susceptibility. Iron is a trace nutrient required for the survival of all organisms and is known to play a critical role during infection. Preliminary data in this proposal demonstrates that 1) neonatal mice infected with E. coli rapidly die from the infection while adults readily clear the disease; 2) neonatal mice mount a rapid and robust anti-microbial response to the infection that is equivalent to the response in adult mice; 3) neonatal mice have increased intraperitoneal total iron that allows for rapid unchecked growth of the E. coli; and 4) targeting this excess intraperitoneal iron improves neonatal survival during E. coli infection. While iron metabolism in adults has been well-described, little is known about iron metabolism during the neonatal period. It is likely that neonates have unique iron metabolism without the full range of iron withholding strategies necessary to prevent infections. The central hypothesis of this proposal is that neonatal mice have increased iron available for bacterial consumption due to a unique mechanism of iron acquisition both during gestation and while breastfeeding as well as altered iron withholding capabilities. The overall goal of this proposal is to target this iron-rich niche to improve survival in neonatal sepsis. This hypothesis will be investigated via the following specific aims: 1) Determine the proportion of increased neonatal available iron that accumulates during gestation versus the proportion that accumulates during breastfeeding; 2) Explore the impact of decreasing intestinal iron absorption and increasing serum transferrin during the neonatal period on neonatal iron status and outcomes in neonatal E. coli sepsis; 3) Determine the impact of inhibiting E. coli iron acquisition systems on outcomes in neonatal E. coli sepsis.