Neonatal immune response to gut originating pathogens

新生儿对肠道来源病原体的免疫反应

• 批准号: 9894407
• 负责人: Kathryn A Knoop
• 金额: $ 23.85万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-18 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894407
• 关键词: Accounting; Address; Adult; Age; Age of Onset; Animal Model; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacterial Translocation; Biological Assay; Birth; Blood; Blood Circulation; Blood specimen; Breast Feeding; CD8-Positive T-Lymphocytes; Caring; Cause of Death; Cecum; Cessation of life; Childhood; Clinical; Cognitive; Data; Development; Disease; Enteral; Enterobacteriaceae; Escherichia coli; Flow Cytometry; Grant; Hour; Human; Hygiene; Immune response; Immune system; Immunosuppression; In Vitro; Incidence; Infant; Infant Care; Infection; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Interleukin 6 Receptor; Interleukin-6; Intervention; Intestines; Intraperitoneal Injections; Intravenous; Kinetics; Leukocytes; Life; Lipopolysaccharides; Lymphocyte; Lymphocyte Activation; Medical Technology; Modeling; Mus; Neonatal; Neonatal Mortality; Newborn Animals; Organ failure; Outcome; Pattern; Perinatal Infection; Peripheral; Premature Infant; Prevention; Production; Respiratory Failure; Risk; Route; Sepsis; Serum; Signal Transduction; Skin; Source; Streptococcus; Surveys; System; Systemic infection; T cell response; T-Cell Activation; Therapeutic; Tissues; Toxin; Translating; Umbilical Cord Blood; Very Low Birth Weight Infant; Virus Diseases; Work; arm; base; cellular targeting; cytokine; cytokine release syndrome; enteric pathogen; fighting; gut bacteria; gut microbiota; human data; immunopathology; improved; in vivo; late onset sepsis; member; mortality; mouse model; neonatal death; neonatal immune system; neonatal sepsis; neonate; novel; older patient; pathogen; pathogenic bacteria; peripheral blood; premature; preterm newborn; pup; response; septic patients; skin microbiota; therapy development; trafficking; trend; Accounting; Address; Adult; Age; Age of Onset; Animal Model; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacterial Translocation; Biological Assay; Birth; Blood; Blood Circulation; Blood specimen; Breast Feeding; CD8-Positive T-Lymphocytes; Caring; Cause of Death; Cecum; Cessation of life; Childhood; Clinical; Cognitive; Data; Development; Disease; Enteral; Enterobacteriaceae; Escherichia coli; Flow Cytometry; Grant; Hour; Human; Hygiene; Immune response; Immune system; Immunosuppression; In Vitro; Incidence; Infant; Infant Care; Infection; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Interleukin 6 Receptor; Interleukin-6; Intervention; Intestines; Intraperitoneal Injections; Intravenous; Kinetics; Leukocytes; Life; Lipopolysaccharides; Lymphocyte; Lymphocyte Activation; Medical Technology; Modeling; Mus; Neonatal; Neonatal Mortality; Newborn Animals; Organ failure; Outcome; Pattern; Perinatal Infection; Peripheral; Premature Infant; Prevention; Production; Respiratory Failure; Risk; Route; Sepsis; Serum; Signal Transduction; Skin; Source; Streptococcus; Surveys; System; Systemic infection; T cell response; T-Cell Activation; Therapeutic; Tissues; Toxin; Translating; Umbilical Cord Blood; Very Low Birth Weight Infant; Virus Diseases; Work; arm; base; cellular targeting; cytokine; cytokine release syndrome; enteric pathogen; fighting; gut bacteria; gut microbiota; human data; immunopathology; improved; in vivo; late onset sepsis; member; mortality; mouse model; neonatal death; neonatal immune system; neonatal sepsis; neonate; novel; older patient; pathogen; pathogenic bacteria; peripheral blood; premature; preterm newborn; pup; response; septic patients; skin microbiota; therapy development; trafficking; trend

Project Abstract Late onset sepsis (LOS), a bloodstream infection and a leading cause of death in newly born babies accounting for 26% of all neonatal deaths, represents a major threat to prematurely born infants. Increased hygiene practices have failed to substantially reduce LOS incidence, which has paradoxically increased in the past forty years due to a continual reduction in the age of viability due to increased medical technology to care for prematurely born infants. Currently, LOS is treated with intravenous antibiotics, but antibiotic resistant bacteria are becoming a greater concern. Additionally, LOS patients are a greater risk for long-term cognitive developmental problems. In a substantial portion of LOS, the pathogen can be found as a resident of the neonatal gut microbial community prior to disease, yet an incomplete understanding as to how LOS initially develops and a lack of an animal model to explore the mechanism, treatment and prevention of LOS onset is a barrier to progress in this field. Moreover, an increasing trend of LOS cases caused by members of the normal skin and intestinal flora, compels the exploration of what defines a sepsis-pathogen. However, it remains unclear: 1) how the enteric pathogen disseminates and 2) the subsequent cause of respiratory and organ failure that contributes to death following LOS. It has been assumed the neonatal response is one of immaturity and ignorance that lacks the ability to properly fight bacterial pathogens due to a state of immunosuppression until the immune system fully matures, resulting in the neonate being overwhelmed by systemic bacterial replication and toxin production. I have developed an animal model, whereby disruption of synchronous breast-feeding results in translocation of gut pathogens from the intestine to the system, resulting in sepsis. I will utilize this model to explore the immune response in the neonate, and translate these findings to the human using peripherally derived leukocytes and lymphocytes from infant blood samples. My hypothesis, in contrast to the current view of neonatal immune responses and based on recent clinical findings of a cytokine signature unique to neonates including increased serum IL-6, is that neonates produce a massive cytokine response following systemic bacterial infections. Additionally, human data revealed sepsis pathogens contribute to the non-specific activation of T cells within 4 hours, suggesting the combination of IL-6 and non-specific activation of lymphocytes may result in a cytokine storm the leads to death. This project will utilize animal models, human blood samples, sepsis pathogens, and a variety of flow cytometry-based assays to explore the immune response to sepsis pathogens. Following the completion of this project, I will understand what the response downstream of systemic bacterial infection in neonates is composed of, which will allow for further exploration into how bacterial components unique to sepsis pathogens cause a massive cytokine response. Also, this work will allow for the development of interventions and preventative therapeutics specific for neonatal sepsis cases, by understanding the unique aspects of the neonatal response.

项目摘要 晚期发作败血症（LOS），血液感染和新生婴儿会计的主要死亡原因 在所有新生儿死亡中，有26％代表着对早产婴儿的主要威胁。卫生实践的增加 未能大大降低LOS的发病率，在过去的四十年中，这种发病率已有矛盾 由于医疗技术的增加而导致可行性的年龄不断减少，以照顾过早出生 婴儿。目前，LOS接受了静脉注射抗生素治疗，但抗生素耐药细菌正在成为一种 更加关心。此外，LOS患者是长期认知发展问题的更大风险。 在大部分LOS中，可以找到病原体作为新生儿肠道微生物群落的居民 在疾病之前 探索LOS发作的机制，治疗和预防是该领域进步的障碍。而且， 正常皮肤和肠菌群成员引起的LOS病例的趋势越来越多，迫使 探索什么定义了败血症。但是，目前尚不清楚：1）肠道病原体如何 传播和2）随后导致呼吸和器官衰竭的原因，导致死亡之后死亡 洛斯。人们认为新生儿反应是不成熟和无知的一种，缺乏能力 由于免疫抑制状态，适当地与细菌病原体作斗争，直到免疫系统完全成熟为止， 导致新生儿被全身细菌复制和毒素产生所淹没。我有 开发了一种动物模型，从而破坏同步母乳喂养会导致肠道易位 病原体从肠道到系统，导致败血症。我将利用此模型探索免疫力 新生儿的反应，并使用外围衍生的白细胞将这些发现转化为人类 来自婴儿血液样本的淋巴细胞。我的假设与新生儿免疫的当前观点相反 反应，并基于最近对新生儿特有的细胞因子特征的临床发现，包括增加 血清IL-6是，在全身细菌感染后，新生儿会产生大量的细胞因子反应。 此外，人类数据揭示了败血症病原体有助于在4中T细胞的非特异性激活 小时，提示IL-6和非特异性淋巴细胞激活的组合可能导致细胞因子 暴风雨导致死亡。该项目将利用动物模型，人类血液样本，败血症病原体和 基于流式细胞术的各种测定法，以探索对败血症病原体的免疫反应。跟随 完成该项目的完成，我将了解系统性细菌感染下游的反应 Neonates由新生儿组成，这将允许进一​​步探索细菌成分如何独特的败血症 病原体会引起大量的细胞因子反应。此外，这项工作将允许发展干预措施 以及针对新生儿败血症病例的预防性治疗剂，通过了解 新生儿反应。