Development of neonatal innate lung defenses is dependent on gastrointestinal commensal bacteria

新生儿先天肺防御能力的发展依赖于胃肠道共生细菌

基本信息

批准号：
10000987
负责人：
Hitesh Deshmukh
金额：
$ 41.76万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000987
关键词：
AGTR2 gene Adoptive Cell Transfers Alveolar Antibiotics Antibodies Bacterial Pneumonia Biological Assay Birth CC chemokine receptor 4 Cell Communication Cell Proliferation Cells Cesarean section Childbirth Complement Dendritic Cells Development Epithelial Epithelial Cell Proliferation Epithelium Exposure to Health Homeostasis Human Immune Immune system Impairment Infant Infection Interruption Intestines Lead Link Lung Lung infections Lymphoid Cell Mediating Microbe Migration Assay Modeling Modernization Mucous Membrane Mus Neonatal Newborn Infant Organoids Pattern Pneumonia Population Predisposition Premature Labor Publications Recombinants Resistance Risk Role Sentinel Signal Transduction Small Intestines Supporting Cell Testing Therapeutic Transgenic Mice base chemokine receptor clinically relevant commensal bacteria design early life exposure epithelial stem cell experimental study fighting fitness gain of function gastrointestinal gut colonization gut microbes improved in vivo interleukin-22 migration mouse model neonatal exposure neonate novel novel therapeutic intervention postnatal postnatal colonization postnatal development postnatal period prevent programs receptor repaired response stem cell proliferation tissue repair trafficking translational impact

项目摘要

PROJECT SUMMARY: Bacterial pneumonia kills more than 1 million newborns each year. Increased neonatal susceptibility to pneumonia is directly linked to immature infant lung mucosal defenses. Colonization by intestinal commensal bacteria, which begins immediately at birth, is hypothesized to be critical for postnatal development of neonate’s immune system, but the underlying mechanisms remain unclear. The premise of this proposal is that early life exposure to commensal bacteria promotes resistance to pneumonia in neonates by accelerating the immune cell development. Modern childbirth practices like increased use of antibiotics to treat preterm labor and cesarean deliveries alter the pattern of intestinal commensal colonization in the newborn and are associated with increased risk of pneumonia. Therefore, understanding this relationship has translational impact. This proposal is based on our recent publications, demonstrating that a rare population of sentinel immune cells- group 3 innate lymphoid cells (ILC3), are critical in defense against bacterial pneumonia in the newborn. A wave of ILC3 populates the murine and human lung in the postnatal period. ILC3 confer protection against bacterial pneumonia in newborn mice. Chemokine receptor, CCR4 was important for lung-specific trafficking of ILC3. This crosstalk was mediated by mucosal dendritic cells (DC), which capture the signals from intestinal commensal bacteria. Disruption of intestinal commensal bacteria with antibiotics abolished the expression of CCR4, interrupted the trafficking of ILC3 into the newborn’s lungs and rendered the antibiotic-treated neonatal mice susceptible to pneumonia in an interleukin (IL)-22 dependent fashion. These findings challenge the current paradigm that commensal bacteria-directed ILC3 development is locally restricted to the small intestine and support the hypothesis that postnatal colonization by intestinal commensal bacteria promotes resistance to pneumonia in neonates by accelerating the development of ILC3 in the newborn lung. The proposed experiments are designed to answer the following fundamental questions regarding the acquisition of pulmonary innate defenses in the newborn. 1) What is the migratory program of lung ILC3 in the newborns? 2) How do intestinal commensal bacteria instruct the migration of ILC3? 3) How do newly migrated ILC3 direct the neonatal pulmonary mucosal defenses against bacterial pneumonia? The proposed studies provide two conceptual advances regarding the development of pulmonary defense in the newborn. First, intestinal colonization by commensal bacteria is necessary for expansion of ILC3 in the newborn lung. Second, the newly expanded pool of ILC3 support lung epithelial stem cell proliferation and regulates pulmonary alveolar repair after pneumonia. These concepts could potentially suggest an alteration to the current practice of empiric broad-spectrum antibiotics in neonates. Our use of developmentally appropriate and clinically relevant murine model is complemented by a novel in vivo ILC3 expansion studies and alveolar organoids to probe ILC3-lung epithelial interactions. Finally, the proposed studies explore therapeutically relevant strategies, for example, commensal bacteria transfer to restore ILC3 development in antibiotic-treated newborns and use recombinant IL22 to promote alveolar repair. These studies will provide a framework to develop new therapeutic strategies to target ILC3 responses and promote lung mucosal defenses in newborns. !

项目摘要：细菌肺炎每年杀死超过100万的新生儿。新生儿对肺炎与未成熟的婴儿肺粘膜防御直接相关。通过肠道定殖细菌在出生时立即开始，假设对新生儿的产后发展至关重要免疫系统，但潜在的机制尚不清楚。该提议的前提是早期接触共生细菌通过加速免疫来促进新生儿肺炎的抗性细胞发育。现代的分娩实践，例如增加使用抗生素治疗早产和剖宫产的实践交付改变了新生儿肠道殖民化的模式，并与增加有关肺炎的风险。因此，理解这种关系已经翻译成影响。该提案基于我们最近的出版物，表明很少有前哨免疫球体人口 3组先天淋巴样细胞（ILC3）对于防御新生儿细菌性肺炎至关重要。波浪 ILC3在产后时期填充了鼠和人类肺。 ILC3防止细菌的会议保护新生小鼠的肺炎。趋化因子受体，CCR4对于ILC3的肺特异性运输很重要。这串扰是由粘膜树突状细胞（DC）介导的，该细胞捕获了肠内的信号细菌。用抗生素破坏肠道传感器细菌消除了CCR4的表达，中断了ILC3贩运新生儿的肺部，并渲染了经过抗生素治疗的新生儿小鼠在白介素（IL）-22依赖性时尚中易受肺炎的影响。这些发现挑战了当前共生细菌指导的ILC3发育局部仅限于小肠，并且支持以下假设，即肠结合细菌的产后定殖促进了对通过加速新生儿肺ILC3的发展，在新生儿中肺炎。拟议的实验旨在回答有关收购的以下基本问题新生儿的肺天防御。 1）新生儿中肺ILC3的迁徙计划是什么？ 2）如何指导ILC3的迁移？ 3）新迁移的ILC3直接如何针对细菌性肺炎的新生儿肺粘膜防御？拟议的研究为肺防御发展提供了两个概念进步新生。首先，对于新生儿中ILC3的扩展是必要的。肺。其次，新扩展的ILC3池支持肺上皮干细胞增殖并调节肺炎后肺肺泡修复。这些概念可能暗示对当前新生儿中经验性广谱抗生素的实践。我们对发展和临床上的发展相关的鼠模型是由新型的体内ILC3扩张研究和肺泡器官完成的探针ILC3肺上皮相互作用。最后，拟议的研究探讨了热相关的策略，例如，共生细菌转移以恢复经抗生素处理的新生儿中的ILC3发育并使用重组IL22以促进肺泡修复。这些研究将为开发新疗法提供一个框架针对ILC3反应并促进新生儿中肺粘膜防御的策略。呢