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Role of gut microbiota-induced IgG in enteric host defense

肠道微生物诱导的 IgG 在肠道宿主防御中的作用

基本信息

批准号：
10671372
负责人：
Melody Y Zeng
金额：
$ 3.81万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671372
关键词：
Antibodies Antigens Bacteria Breast Feeding Citrobacter Citrobacter rodentium Communicable Diseases Ensure Enteral Environment Escherichia coli EHEC Foundations Gnotobiotic Grant Health Host Defense Human Human Milk Human body Immune response Immune system Immunoglobulin G Infection Intestines Investigation Learning Life Mediating Mentors Metabolism Michigan Mission Modeling Moon Morbidity - disease rate Mucous Membrane Mus Neonatal Newborn Infant Nutrient Play Pregnancy Premature Infant Research Role Scientist Sepsis Solid Supervision Symbiosis Systemic infection Testing Therapeutic Training United States National Institutes of Health Universities Vaccines Work antigen test career development enteric infection field study gut bacteria gut microbiota immune resistance improved insight maternal vaccination metabolomics mortality nanoparticle neonatal health neonatal immunity neonatal infection neonatal sepsis neonate novel novel strategies pathogen preterm newborn programs skills therapeutic development vaccine trial

项目摘要

Project Summary/Abstract The gut microbiota has a plethora of important functions that promote human health. The impact of maternal gut microbiota on neonatal health, however, remains largely unknown. Sepsis is an important cause of morbidity and mortality among newborn infants, particularly in preterm infants. Our preliminary studies have unraveled a previously unknown function of the gut microbiota to induce antigen-specific IgG antibodies under homeostatic conditions, which can rapidly mediate clearance of pathogens bearing conserved IgG antigens during systemic infection. Importantly, we found robust levels of commensal-specific IgG antibodies in both mouse and human breast milk. Therefore, our central hypothesis is that 1) maternal commensal IgG confers critical protection to the neonate against infection; 2) maternal immunization with IgG-inducing beneficial gut symbiotic bacteria, or IgG-inducing antigens, may be a novel approach to treat neonatal sepsis, which can be caused by dissemination of gut bacteria. This hypothesis will be tested through three specific aims: 1) determine the role of maternal gut microbiota-induced IgG in neonatal enteric infection, 2) identify and characterize gut symbiotic bacteria that induce homeostatic antigen-specific IgG antibodies, and 3) determine whether maternal immunization with IgG-inducing bacteria or antigens confers protection in the neonate. The objective of the current application is to harness gut microbiota-induced IgG to develop therapeutics for neonatal sepsis, and for the PI to learn new skills such as developing neonatal infection models and vaccine nanoparticles, which are important for her to develop an independent research program with a focus on the gut microbiota and neonatal health. The research is significant because these studies will unravel potentially novel and effective approaches to treat neonatal sepsis. The distinguished mentoring team will allow the PI to complete the proposed studies with new skills and transition to independence in a new field of study. In addition, the excellent research environment of the University of Michigan will provide exceptional support for the proposed studies and the PI's career development.

项目概要/摘要肠道微生物群具有多种促进人类健康的重要功能。产妇的影响然而，肠道微生物群对新生儿健康的影响仍然很大程度上未知。脓毒症是发病的重要原因新生儿，特别是早产儿的死亡率。我们的初步研究揭示了肠道微生物群在稳态条件下诱导抗原特异性 IgG 抗体的先前未知功能条件下，可以在全身过程中快速介导携带保守 IgG 抗原的病原体的清除感染。重要的是，我们在小鼠和人类体内发现了高水平的共生特异性 IgG 抗体母乳。因此，我们的中心假设是 1) 母体共生 IgG 为胎儿提供重要的保护。新生儿抗感染； 2) 使用诱导 IgG 的有益肠道共生菌进行母体免疫，或 IgG 诱导抗原可能是治疗新生儿败血症的一种新方法，新生儿败血症可由以下原因引起：肠道细菌的传播。该假设将通过三个具体目标进行检验：1）确定角色母体肠道微生物群诱导的 IgG 在新生儿肠道感染中的作用，2) 识别和表征肠道共生体诱导稳态抗原特异性 IgG 抗体的细菌，以及 3) 确定母体是否使用 IgG 诱导细菌或抗原进行免疫可为新生儿提供保护。该计划的目标目前的应用是利用肠道微生物诱导的 IgG 来开发新生儿败血症的治疗方法，以及让 PI 学习新技能，例如开发新生儿感染模型和疫苗纳米粒子，这对她来说，开发一个专注于肠道微生物群的独立研究项目很重要，新生儿健康。这项研究意义重大，因为这些研究将揭示潜在的新颖性和有效性治疗新生儿败血症的方法。杰出的指导团队将帮助 PI 完成提议学习新技能并过渡到新研究领域的独立。此外，密歇根大学优良的研究环境将为拟议的研究提供卓越的支持研究和 PI 的职业发展。