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

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