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

• 批准号: 10335227
• 负责人: Melody Y Zeng
• 金额: $ 15.26万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/10335227
• 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

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.

项目摘要/摘要 肠道菌群具有促进人类健康的许多重要功能。产妇的影响 然而，肠道微生物群关于新生儿健康仍然在很大程度上未知。败血症是发病率的重要原因 新生婴儿，特别是早产儿的死亡率。我们的初步研究已经揭示了 肠道微生物群以前未知功能诱导稳态下抗原特异性IgG抗体 条件，可以迅速介导全身性的病原体的轴承抗原的病原体清除 感染。重要的是，我们发现小鼠和人类的共生特异性IgG抗体的强大水平 母乳。因此，我们的核心假设是1）孕产妇的共生IgG赋予了关键保护 反感染的新生儿； 2）具有IgG诱导有益的肠道共生细菌或 IgG诱导抗原，可能是治疗新生儿败血症的一种新型方法，这可能是由 肠道细菌的传播。该假设将通过三个特定目的进行检验：1）确定角色 新生儿肠道感染中孕产妇肠道微生物群诱导的IgG，2）识别和表征肠道共生 诱导稳态抗原特异性IgG抗体的细菌，3）确定母体是否是否 IgG诱导细菌或抗原免疫赋予新生儿的保护。目的 当前的应用是利用肠道菌群诱导的IgG来开发新生儿败血症的疗法，并且 让PI学习新技能，例如开发新生儿感染模型和疫苗纳米颗粒，这是 对于她来说，制定独立研究计划很重要，重点是肠道菌群和 新生儿健康。这项研究很重要，因为这些研究将揭示潜在的新颖和有效 治疗新生儿败血症的方法。杰出的指导团队将允许PI完成 在新的研究领域，提出了新技能和向独立过渡的拟议研究。另外， 密歇根大学出色的研究环境将为拟议的 研究和PI的职业发展。