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: 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
• 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

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. !

项目总结： 细菌性肺炎每年导致100多万新生儿死亡。新生儿更容易患上 肺炎与未成熟的婴儿肺粘膜防御系统直接相关。肠道共生定植 细菌在出生时立即开始，被认为对新生儿的出生后发育至关重要 免疫系统，但潜在的机制仍不清楚。这一提议的前提是早期生命 暴露在共生菌中通过加速免疫来提高新生儿对肺炎的抵抗力 细胞发育。现代分娩做法，如更多地使用抗生素治疗早产和剖腹产 分娩改变了新生儿肠道共生定植的模式，并与增加 患肺炎的风险。因此，理解这种关系具有翻译上的影响。 这一建议是基于我们最近的出版物，证明了一种罕见的哨兵免疫细胞- 第三组先天淋巴样细胞(ILC3)在新生儿细菌性肺炎的防御中起关键作用。一股浪潮 在出生后，ILC3在小鼠和人的肺中大量存在。ILC3提供对细菌的保护 新生小鼠的肺炎。趋化因子受体CCR4对ILC3的肺特异性转运具有重要作用。这 串扰是由粘膜树突状细胞(DC)介导的，DC捕捉来自肠道共融的信号 细菌。用抗生素破坏肠道共生菌取消了CCR4的表达， 阻断ILC3进入新生儿肺的运输，并使接受抗生素治疗的新生小鼠 以白介素22依赖的方式易患肺炎。这些发现挑战了当前的 以共生细菌为导向的ILC3发育局限于小肠和 支持肠道共生菌在出生后定植可促进抗药性的假设 通过加速ILC3在新生儿肺内的发展而导致新生儿肺炎。 拟议的实验旨在回答有关收购的以下基本问题 新生儿的肺脏先天防御系统。1)新生儿肺中ILC3的迁移计划是什么？ 2)肠道共生菌如何指导ILC3的迁移？3)新迁移的ILC3如何引导 新生儿肺粘膜对细菌性肺炎的防御？ 拟议的研究提供了两个关于肺防御发展的概念性进展。 刚出生的。首先，肠道共生菌的定植对于新生儿ILC3的扩张是必要的。 阿龙。第二，新扩大的ILC3池支持肺上皮干细胞增殖并调节 肺炎后的肺泡修复。这些概念可能潜在地暗示着对当前 经验性广谱抗生素在新生儿中的应用。我们在发育方面和临床上的使用 相关的小鼠模型得到了一项新的体内ILC3扩张研究和肺泡有机化合物的补充 探讨ILC3与肺上皮细胞的相互作用。最后，建议的研究探索与治疗相关的策略， 例如，共生菌转移以恢复接受抗生素治疗的新生儿的ILC3发育并使用 重组人白介素22促进牙槽骨修复这些研究将为开发新的治疗方法提供一个框架 针对ILC3反应和促进新生儿肺粘膜防御的策略。 好了！