Microbiota Regulation of Pulmonary Complications Post-HCT

HCT 后肺部并发症的微生物群调节

基本信息

批准号：
10205471
负责人：
Xiaofeng Zhou
金额：
$ 38.16万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/10205471
关键词：
16S ribosomal RNA sequencing Acute Address Allogenic Anaerobic Bacteria Animal Model Antibiotics Antiviral Agents Area Autoimmune Diseases Bacteria Butyrates C Type Lectin Receptors Cell physiology Chronic 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 Inflammation 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 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 reactivation from latency response

项目摘要

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

项目概要造血细胞移植（HCT）是治疗多种肿瘤性疾病的潜在疗法。然而，在 HCT 改变或生态失调过程中，微生物群的组成经常受到干扰。 HCT 后肺部微生物组的变化与不良的临床结果相关，包括肺损伤。并发症通常发生在 HCT 接受者中，是 HCT 后发病的主要原因这些肺部并发症包括由传染源引起的病理以及呼吸道疾病。所谓的“非感染性”疾病非感染性肺部并发症与不可逆转的疾病有关。肺功能障碍和相当大的死亡率无法治愈这些进行性疾病，例如特发性肺炎综合征（IPS），其特征是肺炎、肺损伤和纤维化。对 HCT 后非感染性肺部疾病的病因和发病机制知之甚少，研究也很少在这一领域，我们的长期目标是改善 HCT 接受者的治疗结果。通过开发基于微生物组的治疗策略来管理 HCT 后肺部并发症。我们已经证明，潜伏疱疹病毒的原发感染或重新激活会增加 HCT 后肺部感染的风险 IPS 等损伤，并且这些肺损伤与人类 HCT 中肺微生物群的失调有关我们开发了新的动物模型来概括 IPS 的病理特征，以允许机制研究表明，乳酸杆菌和毛螺菌科的数量减少。小鼠家族与 IPS 样肺炎和纤维化的发生有关，并且 HCT 和疱疹病毒感染后的肺炎和纤维化依赖于 IL-17，重要的是，微生物群被分离。来自 HCT 小鼠肺部的 IL-17 前体可能通过肺树突状细胞 (DC) 产生反应损害Notch配体、δ样配体4 (DLL4)的表达因此，我们追求HCT改变。肺微生物群促进肺 DC 修饰/启动，从而使 DC 促进致病性 IL-17 反应疱疹病毒感染导致肺部病变和 IPS 等肺部并发症的发生。将在该拟议项目中实现以下三个具体目标。目标 1. 确定与 HCT 后肺部并发症相关的关键肺部微生物群目标 2. 确定肺微生物群调节肺 DC 功能的机制目标 3. 确定乳杆菌属和毛螺菌科在发育中的作用 HCT 后肺部并发症的发生率