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.

项目总结/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在很大程度上仍然未知。脓毒症是发病的重要原因 以及新生儿，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下诱导抗原特异性IgG抗体的先前未知功能 条件，其可以在全身性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，我们在小鼠和人类中发现了大量的肠道特异性IgG抗体， 母乳。因此，我们的中心假设是：1）母体血清IgG赋予关键的保护， 新生儿抗感染; 2）用IgG诱导的有益肠道共生菌对母体进行免疫，或 IgG诱导抗原可能是治疗新生儿败血症的一种新方法， 肠道细菌的传播。这一假设将通过三个具体目标进行检验：1）确定角色 新生儿肠道感染中母体肠道微生物群诱导的IgG，2）识别和表征肠道共生菌 细菌，诱导稳态抗原特异性IgG抗体，和3）确定是否母体 用IgG诱导细菌或抗原免疫可在新生儿中提供保护。的目的 当前的应用是利用肠道微生物群诱导的IgG来开发新生儿败血症的治疗剂， PI学习新技能，如开发新生儿感染模型和疫苗纳米颗粒， 对她来说，重要的是要制定一个独立的研究计划，重点是肠道微生物群， 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和有效的 治疗新生儿败血症的方法。杰出的指导团队将允许PI完成 建议学习新技能，并在新的研究领域过渡到独立。此外该 密歇根大学优良的研究环境将为拟议的 研究和PI的职业发展。