Role of gut microbiota-induced IgG in enteric host defense

项目摘要/摘要 肠道微生物区系具有许多促进人类健康的重要功能。母体的影响 然而，肠道微生物区系对新生儿健康的影响在很大程度上仍不清楚。脓毒症是发病的重要原因。 和新生儿死亡率，特别是早产儿。我们的初步研究揭开了一个 肠道微生物区系在体内平衡状态下诱导抗原特异性抗体的功能未知 条件，可以迅速调解清除携带保守的免疫球蛋白抗原的病原体 感染。重要的是，我们在小鼠和人类中都发现了强大的共生体特异性抗体。 母乳。因此，我们的中心假设是：1)母体共生免疫球蛋白对 新生儿抗感染；2)用免疫球蛋白诱导有益肠道共生菌进行母体免疫；或 免疫球蛋白诱导抗原，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 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区系诱导免疫球蛋白的研究2)肠道共生菌的鉴定和表征 诱导动态平衡抗原特异性抗体的细菌，以及3)决定母亲是否 用免疫球蛋白诱导细菌或抗原免疫对新生儿有保护作用。该计划的目标是 目前的应用是利用肠道微生物区系诱导的免疫球蛋白来开发治疗新生儿败血症的药物，以及 对于PI来说，学习新的技能，如开发新生儿感染模型和疫苗纳米颗粒， 对她来说很重要的是制定一个独立的研究计划，重点是肠道微生物区系和 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 新生儿败血症的治疗方法。杰出的指导团队将允许PI完成 建议在一个新的研究领域采用新技能并过渡到独立学习。此外， 密歇根大学良好的研究环境将为拟议的 学习和私家侦探的职业发展。

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.