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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.

项目总结