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：
10055119
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/10055119
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 Epithelium 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.

项目概要新生儿败血症是血液感染导致新生儿死亡的主要原因由多种细菌性病原体引起。尽管卫生习惯有所提高，LOS 发生率仍呈下降趋势矛盾的是，在过去四十年中，由于共生物种引起的病例增加，该病例有所增加来自正常皮肤和肠道菌群。有趣的是，在 LOS 的很大一部分中，病原体可以在患病前被发现是新生儿肠道微生物群落的居民，但目前尚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做出反应起源病原体易位。在我的初步研究中，我已经表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）并需要 CX3CR1 单核吞噬细胞 (MNP) 进入循环系统。一天前细菌易位生命 10 受到母乳中母体提供的蛋白质的抑制。异步交叉培育 (ACF) 为 1 10天前生下一窝幼崽的一日龄幼崽会导致DOL1-之间的细菌易位多尔10。共生细菌和致病性临床败血症分离株都可能易位并获得 ACF 小鼠的全身生理通路。然而，只有喂食致病性大肠杆菌的小鼠才会死亡尽管细菌负担相似，但致病性大肠杆菌易位后会导致类似败血症的疾病与带有共生大肠杆菌的 ACF 小鼠相比。带有致病性大肠杆菌的 ACF 小鼠出现炎症肠道固有层中的特征，并且由 CX3CR1+ MNP 产生的全身性 IL6 增加，表明粘膜对易位共生体和病原体有不同反应的机制免疫系统。人们认为新生儿的反应是一种不成熟和无知，缺乏由于免疫抑制状态而正确对抗细菌病原体的能力，直到免疫系统完全恢复成熟。然而，我的初步数据表明，复杂的先天免疫系统能够感知不同的细菌差异并感知潜在的致病威胁。我的假设基于最近的临床发现新生儿特有的细胞因子特征（包括血清 IL-6 增加）的一个特点是，这种反应是由肠道内遇到易位细菌的 MNP 细胞。该项目将利用动物模型、脓毒症病原体和各种基于流式细胞术的检测，以探索先天免疫对从肠道转移后的败血症病原体的反应。此项工作完成后项目，我将了解病原体易位后的先天免疫反应，定义动态 CX3CR1 MNP 如何促进细菌的系统传播，以及这些过程如何可能与共生易位后的反应不同。此外，这项工作将允许制定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来源细菌病原体反应的独特方面。