Microbiota Regulation of Pulmonary Complications Post-HCT

HCT 后肺部并发症的微生物群调节

• 批准号: 10491061
• 负责人: Xiaofeng Zhou
• 金额: $ 39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491061
• 关键词: 16S ribosomal RNA sequencing; Acute; Address; Allogenic; Anaerobic Bacteria; Animal Model; Antibiotics; Area; Autoimmune Diseases; Bacteria; Butyrates; C Type Lectin Receptors; Cell physiology; Chronic Lung Injury; Cidofovir; Clinical; Complication; Data; Dendritic Cells; Development; Dexamethasone; Disease; Effectiveness; Etiology; Family; Fibrosis; Functional disorder; Germ-Free; Goals; Herpesviridae; Human; Idiopathic pneumonia syndrome; Immune response; Impairment; Infection; Infectious Agent; Inflammation; Injury; Interleukin-17; Lactobacillus; Lead; Ligands; Link; Lung; Lung Transplantation; Lung diseases; Lytic Phase; Malignant Neoplasms; Mediating; Metagenomics; Mission; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Pre-Clinical Model; Primary Infection; Process; Pulmonary Fibrosis; Pulmonary Inflammation; Pulmonary Pathology; Regulation; Research; Risk; Role; Stem cell transplant; Techniques; Testing; Therapeutic; Toll-like receptors; Transplant Recipients; Transplanted Lung Complication; United States National Institutes of Health; Viral; Virus; Virus Diseases; Work; adaptive immunity; bacterial community; base; curative treatments; dysbiosis; hematopoietic cell transplantation; improved outcome; lung development; lung injury; lung microbiome; lung microbiota; microbial community; microbiome; microbiota; microbiota transplantation; mortality; neoplastic; notch protein; novel; pneumonitis and fibrosis; reactivation from latency; response

Project Summary Hematopoietic cell transplantation (HCT) is a potentially curative therapy for a variety of neoplastic disorders. However, the composition of the microbiota is often disturbed during the process of HCT. Alterations or dysbiosis of the lung microbiome post-HCT are associated with poor clinical outcomes, including lung injury. Pulmonary complications commonly occur among HCT recipients and are a leading cause of post-HCT morbidity and mortality. These pulmonary complications include both pathologies generated by infectious agents and also the so called “non-infectious” disorders. Non-infectious pulmonary complications are associated with irreversible pulmonary dysfunction and considerable mortality. No cure exists for these progressive disorders such as idiopathic pneumonia syndrome (IPS) which is characterized by pneumonitis, lung injury and often fibrosis. The etiology and pathogenesis of non-infectious post-HCT pulmonary disorders is poorly understood and research in this area is a critical need within the NIH mission. Our long-term goal is to improve outcomes for HCT recipients by developing microbiome-informed therapeutic strategies to manage post-HCT pulmonary complications. We have shown that primary infection or reactivation of latent herpesviruses increases the risk of post-HCT lung injury such as IPS and that these lung injuries are associated with dysbiosis of lung microbiota in human HCT recipients. We have developed novel animal models that recapitulate the pathologic features of IPS to allow for mechanistic studies. We have shown that a loss in abundance of Lactobacillus species and the Lachnospiraceae family in mice is associated with developing IPS-like pneumonitis and fibrosis, and that the development of pneumonitis and fibrosis post-HCT and herpesviral infection is IL-17-dependent. Importantly, microbiota isolated from the lungs of HCT mice stimulate pro-IL-17 responses by lung dendritic cells (DCs) potentially through impairing the expression of Notch ligand, delta like ligand 4 (DLL4). Thus, we hypothesize that HCT-altered lung microbiota facilitate lung DC modifications/priming so that DCs promote pathogenic IL-17 responses to herpes virus infection leading to lung pathology and the development of pulmonary complications like IPS. We will pursue the following three specific aims in this proposed project. Aim 1. Identify key lung microbiota associated with post-HCT pulmonary complications Aim 2. Determine the mechanism(s) through which lung microbiota regulate lung DC function Aim 3. Determine the role of Lactobacillus species and the Lachnospiraceae family in the development of post-HCT pulmonary complications

项目摘要 造血细胞移植（HCT）是多种肿瘤疾病的潜在治疗疗法。 但是，在HCT过程中，菌群的组成通常会受到干扰。改变或营养不良 HCT后肺微生物组的肺部与临床结局不良有关，包括肺损伤。肺 HCT接受者通常发生并发症，是HCT后发病率的主要原因和 死亡。这些肺并发症包括传染剂产生的病理，也包括 所谓的“非感染”疾病。非感染性肺并发症与不可逆 肺功能障碍和相当大的死亡率。这些进展障碍（例如 特发性肺炎综合征（IPS），其特征是肺炎，肺损伤和纤维化。这 非感染后HCT肺部疾病的病因和发病机理知之甚少和研究 在这一领域，NIH任务中的至关重要。我们的长期目标是改善HCT接收者的结果 通过制定微生物组知识疗法的策略来管理HCT后肺并发症。 我们已经表明，潜在疱疹病毒的原发性感染或重新激活增加了HCT肺后的风险 IPS等损伤，这些肺损伤与人类HCT中肺微生物群的营养不良有关 收件人。我们开发了新型的动物模型，这些模型概括了IP的病理特征以允许 机械研究。我们已经表明，乳杆菌物种和lachnospileceae的抽象损失 小鼠中的家族与患IPS样肺炎和纤维化有关，并发展 HCT和疱疹病毒感染后肺炎和纤维化是IL-17依赖性的。重要的是，菌群分离出来 从HCT小鼠的肺中 损害了Notch配体的表达，Delta像配体4（DLL4）。那我们假设这是改变了HCT的 肺微生物群喜欢的肺直流修饰/启动，以便DC促进致病性IL-17对 疱疹病毒感染导致肺病理和IPS等肺并发症的发展。我们 将在该拟议项目中追求以下三个特定目标。 目标1。识别与HCT后肺并发症相关的关键肺微生物群 目标2。确定肺微生物群调节肺直流功能的机制 目标3。确定乳酸菌物种和lachnospileaceae家族在发育中的作用 HCT后肺并发症