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

• 批准号: 10468894
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468894
• 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; 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 repair; 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; neonatal mice; 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

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. !

项目概要： 每年有100多万新生儿死于细菌性肺炎。增加新生儿对 肺炎与不成熟的婴儿肺粘膜防御直接相关。肠道细菌定植 细菌，在出生时立即开始，被假设为对新生儿的出生后发育至关重要。 免疫系统，但潜在的机制尚不清楚。这个提议的前提是， 暴露于肠道细菌可通过加速新生儿的免疫反应， 细胞发育现代分娩实践，如增加使用抗生素治疗早产和剖宫产 分娩改变了新生儿肠道细菌定植的模式， 肺炎的风险。因此，理解这种关系具有翻译影响。 这个建议是基于我们最近的出版物，证明了一个罕见的哨兵免疫细胞群体- 第3组先天性淋巴样细胞（ILC 3）在新生儿细菌性肺炎的防御中至关重要。一波 ILC 3的表达在出生后时期在鼠和人肺中存在。ILC 3提供针对细菌的保护 新生小鼠的肺炎。趋化因子受体CCR 4对ILC 3的肺特异性运输起重要作用。这 串话是由粘膜树突状细胞（DC）介导的，DC捕获来自肠粘膜的信号， 细菌用抗生素破坏肠道细菌可消除CCR 4的表达， 阻断ILC 3进入新生鼠肺的运输， 易受白细胞介素（IL）-22依赖性肺炎的影响。这些发现挑战了目前 肠道细菌介导的ILC 3发育局部局限于小肠， 支持出生后肠道细菌定植促进对 通过加速ILC 3在新生儿肺中的发展，可以在新生儿中预防肺炎。 所提出的实验旨在回答以下有关获取的基本问题 新生儿肺部的先天防御系统。1)新生儿肺ILC 3的迁移程序是什么？ 2)肠道细菌如何指导ILC 3的迁移？3)新迁移的ILC 3如何引导 新生儿肺粘膜对细菌性肺炎的防御能力 这些研究提供了两个概念上的进展，关于肺防御的发展， 新生儿。首先，肠道细菌的定植对于ILC 3在新生儿中的扩增是必要的 肺。第二，新扩增的ILC 3库支持肺上皮干细胞增殖并调节 肺炎后肺泡修复这些概念可能会改变目前的 新生儿经验性广谱抗生素的应用。我们在临床上使用适合发育的 相关的鼠模型由新的体内ILC 3扩增研究和肺泡类器官补充， 探针ILC 3-肺上皮相互作用。最后，拟议的研究探索了治疗相关的策略， 例如，肠道细菌转移以恢复治疗的新生儿中的ILC 3发育， 重组IL 22促进肺泡修复。这些研究将为开发新的治疗方法提供一个框架。 靶向ILC 3反应和促进新生儿肺粘膜防御的策略。 !