Targeting iron to improve outcomes in neonatal Escherichia coli sepsis

以铁为靶点改善新生儿大肠杆菌败血症的预后

• 批准号: 10337026
• 负责人: Jennifer Bermick
• 金额: $ 38.64万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-05 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337026
• 关键词: Adult; Allergic Disease; Antibiotic Therapy; Antibiotics; Asthma; Autoimmune Diseases; Bacteria; Biological Markers; Birth; Blood Volume; Brain; Breast Feeding; Cattle; Cells; Cessation of life; Childhood; Consumption; Critical Illness; Data; Defect; Deferoxamine; Developing Countries; Development; Diagnosis; Diet; Dietary Iron; Disease; Enteral; Erythrocytes; Escherichia coli; Escherichia coli Infections; Fostering; Gallium; Glutamine; Goals; Gram-Negative Bacteria; Greater sac of peritoneum; Growth; Human Milk; Immune; Immune response; Immune system; Incidence; Infection; Infection prevention; Intake; Intestines; Iron; Iron Isotopes; Iron Uptake Inhibition; Lactation; Lactoferrin; Lead; Life; Measurement; Measures; Metabolic; Morbidity - disease rate; Mus; Necrotizing Enterocolitis; Neonatal; Neonatal Mortality; Organism; Outcome; Passive Immunization; Peritoneal; Play; Predisposition; Pregnancy; Premature Infant; Recycling; Research; Risk; Role; SLC11A2 gene; Sepsis; Serum; Siderophores; Signs and Symptoms; Source; Supplementation; System; Tissues; Trace Elements Nutrition; Transferrin; United States; Virulent; Wheezing; Work; antimicrobial; clinically relevant; combat; dietary excess; early onset; experimental study; fitness; global health; improved; improved outcome; infancy; intestinal barrier; intraperitoneal; iron absorption; iron metabolism; microbiome; mortality; mouse model; neonatal infection; neonatal mice; neonatal period; neonatal sepsis; neonate; pathogen; pathogenic Escherichia coli; prevent; pup; rapid growth; receptor; response; senescence; siderophore receptors; success; therapeutic target; uptake

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.

项目概要/摘要 感染是新生儿期死亡的主要原因。早发性败血症 (EOS)，发生 出生后3-5天内的死亡率约为25%。大肠杆菌 (E. coli) 是其中之一 足月儿和早产儿 EOS 的主要原因。及时开始使用抗生素对于生存至关重要 在 EOS 中，但具有挑战性，因为 EOS 表现出非特异性体征和症状，没有可靠的证据 帮助诊断的生物标志物。对所有危重新生儿进行经验性抗生素治疗是有问题的，因为 不必要的抗生素暴露与许多短期和长期发病有关，包括 坏死性小肠结肠炎、出生后五天后的败血症以及出生后持续性喘息和哮喘 童年。这凸显了寻找其他疗法来治疗 EOS 的必要性。历史上，新生儿 对感染的易感性被归因于免疫系统发育“不成熟”。然而， 最近的研究表明，新生儿先天免疫细胞可以产生强大而有效的免疫 在许多情况下的反应。这表明需要对免疫细胞独立缺陷进行更多研究 这可能会增加新生儿感染的易感性。铁是所有生命体生存所需的微量营养素 生物体，已知在感染过程中发挥关键作用。该提案中的初步数据表明 1）感染大肠杆菌的新生小鼠很快就会因感染而死亡，而成年小鼠则很容易清除疾病； 2） 新生小鼠对感染产生了快速而强大的抗微生物反应，其效果相当于 成年小鼠的反应； 3) 新生小鼠腹腔内总铁含量增加，可以快速 大肠杆菌不受控制的生长； 4) 针对腹腔内过量的铁可提高新生儿的存活率 在大肠杆菌感染期间。虽然成人的铁代谢已得到很好的描述，但人们对铁知之甚少 新生儿时期的新陈代谢。新生儿很可能具有独特的铁代谢，但没有完全的铁代谢。 预防感染所需的一系列铁保留策略。本提案的中心假设 新生小鼠由于独特的机制而增加了可用于细菌消耗的铁 妊娠期间和母乳喂养期间铁的获取机制以及铁的改变 扣留能力。该提案的总体目标是针对这个富含铁的利基市场，以改善 新生儿败血症的生存率。该假设将通过以下具体目标进行研究：1）确定 妊娠期间积累的新生儿可用铁增加的比例与 母乳喂养期间积累； 2) 探索减少肠道铁吸收的影响 新生儿期血清转铁蛋白升高对新生儿铁状态和新生儿结局的影响 大肠杆菌败血症； 3) 确定抑制大肠杆菌铁获取系统对新生儿大肠杆菌结局的影响。 大肠杆菌败血症。