权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Innate Immune Response Following Bacterial Translocation in Early Life

生命早期细菌易位后的先天免疫反应

基本信息

批准号：
10214603
负责人：
Kathryn A Knoop
金额：
$ 11.93万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-10 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214603
关键词：
Address Animal Model Antigens Bacteria Bacterial Infections Bacterial Model Bacterial Translocation Biological Assay Birth Blood Circulation Cardiovascular system Cause of Death Cells Cessation of life Childhood Clinical Cognitive Data Development Disease Enteral Epithelial Escherichia coli Flow Cytometry Fostering Goblet Cells Grant Human Milk Hygiene IL6 gene ITGAM gene Immune system Immunosuppression Incidence Infant Infection Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Innate Immune Response Innate Immune System Interleukin-6 Intestines Lamina Propria Life Ligands Mononuclear Multiple Organ Failure Mus Nature Neonatal Newborn Animals Organ Organ failure Pathogenicity Perinatal Infection Phagocytes Physiological Population Process Proteins Risk Role Route Sepsis Serum Signal Pathway Therapeutic Time Virulence Virus Diseases Weaning Work base colon bacteria commensal bacteria cytokine fighting gut microbiota immunopathology immunosuppressed intestinal epithelium intraperitoneal late onset sepsis mesenteric lymph node mortality neonatal death neonatal immune system neonatal sepsis neonate older patient pathogen pathogenic Escherichia coli pathogenic bacteria pup response skin microbiota therapy development

项目摘要

Project Summary Neonatal sepsis is a leading cause of death in newly born babies resulting from a bloodstream infection caused by a variety of bacterial pathogens. Despite increased hygiene practices, LOS incidence has paradoxically increased in the past forty years due to an increase in cases resulting from commensal species from the of the normal skin and intestinal flora. Intriguingly, in a substantial portion of LOS, the pathogen can be found as a resident of the neonatal gut microbial community prior to disease, yet it remains unclear how bacterial pathogens translocate from the intestine and how the neonatal immune system initially reacts to gut originating pathogen translocation. In my preliminary studies, I have shown gut residing bacteria can translocate the epithelium via goblet cells forming goblet cell associated antigen passages (GAPs) and require CX3CR1 mononuclear phagocytes (MNPs) to gain access to the circulation. Bacterial translocation prior to day of life 10 is inhibited by maternally supplied proteins in breastmilk. Asynchronous cross-fostering (ACF) of 1 day old pups to dams having delivered a litter 10 days prior results in bacterial translocation between DOL1- DOL10. Both commensal bacteria and pathogenic clinical sepsis-causing isolates could translocate and gain systemic access physiologically In ACF mice. However, only mice gavaged with pathogenic E.coli succumbed to a sepsis-like disease following translocation of pathogenic E.coli, despite similar bacteria burden when compared to ACF mice with commensal E. coli. ACF mice with pathogenic E.coli, developed an inflammatory signature in the intestinal lamina propria and had increased systemic IL6, produced by CX3CR1+ MNPs, suggesting a mechanism to differentially respond to translocation commensals and pathogens by the mucsoal immune system. 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. However, my preliminary data indicates a sophisticated innate immune system able to sense distinct bacterial differences and perceive potential pathogenic threats. My hypothesis based on recent clinical findings of a cytokine signature unique to neonates including increased serum IL-6 is that this response is initiated by the MNP cells within the intestine that encounter the translocating bacteria. This project will utilize animal models, sepsis pathogens, and a variety of flow cytometry-based assays to explore the innate immune response to sepsis pathogens following translocation from the intestine. Following the completion of this project, I will understand the innate immune response following pathogen translocation, defining the dynamics of how CX3CR1 MNPs may contribute to systemic dissemination of bacteria, and how these processes may differ from the response following commensal translocation. Additionally, 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 to gut originating bacterial pathogens.

项目摘要新生儿败血症是新生儿血液感染导致死亡的主要原因由多种细菌病原体引起。尽管卫生习惯有所增加，但LOS发生率在过去的四十年里，由于由寄生虫引起的病例增加，从正常皮肤和肠道植物群中分离。有趣的是，在LOS的很大一部分，病原体可以作为新生儿肠道微生物群落的居民在疾病发生前被发现，但仍不清楚如何细菌病原体从肠道转移，以及新生儿免疫系统最初如何对肠道引发病原体移位在我的初步研究中，我已经证明肠道细菌可以通过杯状细胞易位上皮，形成杯状细胞相关抗原通道（GAP）， CX 3CR 1单核吞噬细胞（MNP）进入循环。日前细菌移位母乳中由母体提供的蛋白质抑制了10岁的生命。1的异步交叉培养（ACF） 1日龄幼仔与10天前分娩的母鼠之间的细菌易位导致DOL 1- DOL10.肠道细菌和致病性临床脓毒症菌株均能移位并获得 ACF小鼠的全身生理学通路。然而，只有灌胃致病性大肠杆菌的小鼠死亡，致病性大肠杆菌易位后的败血症样疾病，尽管当对照组与感染E.杆菌感染致病性大肠杆菌的ACF小鼠，在肠固有层中的签名，并增加了由CX 3CR 1 + MNP产生的全身性IL 6，这表明粘膜对易位病原体和病原体的不同反应机制，免疫系统人们一直认为新生儿的反应是不成熟和无知的，由于免疫抑制状态，直到免疫系统完全恢复，成熟然而，我的初步数据表明，一个复杂的先天免疫系统能够感知不同的细菌的差异和感知潜在的致病威胁。我的假设基于最近的临床发现包括血清IL-6升高在内的新生儿特有的细胞因子特征的一个重要原因是，这种反应是由肠道内的MNP细胞遇到易位细菌。该项目将利用动物模型，败血症病原体，以及各种基于流式细胞术的检测，以探索先天免疫从肠移位后对脓毒症病原体的反应。在完成这项工作后，项目，我将了解病原体易位后的先天免疫反应，定义动态 CX 3CR 1 MNP如何促进细菌的全身传播，以及这些过程如何与染色体易位后的反应不同。此外，这项工作将允许开发针对新生儿败血症病例的干预措施和预防性治疗方法，了解新生儿对肠道源性细菌病原体反应的独特方面。