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.

项目总结/摘要 感染是新生儿期死亡的主要原因。早发性脓毒症（EOS）， 在出生后的前3-5天内，死亡率约为25%。大肠埃希菌（E.大肠杆菌）是一种 足月儿和早产儿EOS的主要原因。及时开始使用抗生素对生存至关重要 但具有挑战性，因为EOS表现为非特异性体征和症状， 生物标志物来帮助诊断。经验性抗生素治疗所有危重新生儿是有问题的， 不必要的抗生素暴露与许多短期和长期的发病率有关，包括 坏死性小肠结肠炎，败血症超过前五天的生活和持续喘息和哮喘， 童年.这突出了需要确定治疗EOS的其他疗法。历史上，新生儿 对感染的易感性归因于免疫系统发育的“不成熟”。然而，在这方面， 最近的研究表明，新生儿的先天免疫细胞可以产生强大而有效的免疫反应， 在许多情况下的反应。这表明需要对免疫细胞非依赖性缺陷进行更多研究 可能导致新生儿感染易感性。铁是所有人生存所需的微量营养素 已知在感染过程中起关键作用。本提案中的初步数据表明， 1）新生小鼠感染E.大肠杆菌感染后很快死亡，而成年人很容易清除疾病; 2） 新生小鼠对感染产生了快速而强烈的抗微生物反应， 3）新生小鼠腹腔内总铁增加，允许快速 E.大肠杆菌;和4）针对这种过量的腹膜内铁提高新生儿存活率 在E.大肠杆菌感染。虽然铁在成人的代谢已被很好地描述，很少有人知道铁 新生儿时期的新陈代谢。新生儿很可能有独特的铁代谢， 一系列预防感染所需的铁抑制策略。这项提议的核心假设是 新生小鼠具有增加的可用于细菌消耗的铁， 妊娠期和哺乳期获得铁的机制以及铁的改变 保留能力。这项提案的总体目标是针对这一富含铁的利基市场， 新生儿败血症的存活率。将通过以下具体目标对这一假设进行研究：1）确定 在妊娠期间积累的新生儿有效铁增加的比例与 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营养状况及新生儿E. 3）测定抑制大肠杆菌败血症的作用。coli铁获取系统对新生儿E. 大肠杆菌败血症。