Interleukin-27 in host response to Legionella infection

Interleukin-27 在宿主对军团菌感染的反应中

基本信息

批准号：
10745091
负责人：
Markus Bosmann
金额：
$ 70.37万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745091
关键词：
Ablation Accidents Acute Acute Respiratory Distress Syndrome Adoptive Cell Transfers Aerosols Alveolar Macrophages Amoeba genus Antibodies Bacteria Binding Body Weight decreased Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Cell Communication Cell Maturation Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cessation of life Chimera organism Chimeric Proteins Chronic Clinical Cytoprotection Data Defect Dendritic Cells Dimensions Disease Engineering Environment Family Future Gene Deletion Genetic Transcription Habitats Histology Human IL27RA gene ITGAM gene Immune Immune response Immunologic Receptors Immunosuppression Impairment Incidence Infection Infiltration Inflammation Inflammatory Response Inhalation Interferon Type II Interleukin-12 Interleukin-6 Interleukins Invaded Knock-out Knowledge Legionella Legionella longbeachae Legionella pneumophila Legionellaceae Legionellosis Legionnaires&apos Disease Ligation Lung Lung infections Lymphocyte Macrophage Mediating Mediator Molecular Mononuclear Mus Myeloid Cells NK Cell Activation Natural Killer Cells Neutrophil Infiltration Outcome PD-1/PD-L1 Parasites Pathogenesis Pathway interactions Patients Pattern recognition receptor Phagocytes Phagocytosis Phosphoproteins Phosphorylation Play Pneumonia Production Receptor Activation Regulatory T-Lymphocyte Reporter Reporting Research Resistance Respiratory physiology Role STAT1 gene STAT3 gene Sampling Severities Signal Pathway Signal Transduction Solid Source Surrogate Endpoint T cell response T-Cell Activation T-Lymphocyte Testing United States Vacuole Virulent Wild Type Mouse atypical pneumonia cell type cytokine experimental study high risk immunopathology improved innate immune sensing insight monocyte mortality multidimensional data novel organ injury pathogen programs protein biomarkers receptor targeted treatment transcriptome γδ T cells

项目摘要

Project Summary: Legionellosis (Legionnaires’ disease) is a form of atypical pneumonia with a steep rising incidence in the United States. The mortality rates of patients stagnate around 3-30% despite treatment. Legionellosis is caused by facultative, intracellular bacteria of the Legionellaceae family, which reside in natural and engineered aquatic habitats. Inhalation of contaminated aerosols can lead to infection, evasion of pathogen eradication and continuous replication in Legionella containing vacuoles inside alveolar macrophages (AMs). The ensuing inflammation promotes an infiltration of myeloid cells and lymphocytes into lungs. These immune cells communicate with each other via cytokines. Interleukin-27 (IL-27) is a heterodimeric cytokine formed by non-covalent interactions of the subunits p28 and EBI3. IL-27 is induced by pattern recognition receptor (PRR) activation in mononuclear phagocytes (AMs, monocytes, dendritic cells). IL-27 ligation with its unique receptor chain, IL-27RA, on lymphocytes initiates STAT1/STAT3 phosphorylation. IL-27RA signaling initiates pleiotropic programs, which can first intensify acute inflammation and later limit prolonged T cell activation. Our preliminary data support the new concept that IL-27 is a critical player of the host response to Legionella infection. IL-27 is elevated in broncho-alveolar lavage fluids of human patients with Legionnaires’ disease and IL-27RA deficient mice are more resistant to infection. Here, we propose to test the central hypothesis that IL-27 is produced by Legionella infected mononuclear phagocytes and initiates dichotomous programs in lymphocytes, that include the protective activation of NK cells and adverse T cell-mediated immunosuppression in lungs. Aim 1) To pinpoint the cellular source(s) of IL-27 during Legionellosis within the subsets of lung mononuclear phagocytes. We aim to assess the contribution of relevant PRR immunosensors for IL-27 induction by L. pneumophila. Samples from Legionnaires’ disease patients will be studied for associations of IL-27 with the PD-1/PD-L1 axis and soluble markers of immunopathology. Aim 2) To characterize the functional consequences of constitutive IL-27RA ablation in infected IL-27RA-/- mice, and to study the host response programs by single-cell, multi-dimensional proteotranscriptomics (CITE-Seq/Total-Seq). We will also evaluate neutralizing IL-27 antibodies and an engineered decoy receptor to improve pneumonia severity in mice. Aim 3) Based on preliminary data, we aim to study the altered inflammatory response of our novel conditional mice with NK cell-specific deletion of IL-27RA. We will investigate whether NK cell maturation is associated with a switch of IL-27RA controlled transcriptional programs through engaging non-STAT phosphoprotein signaling. Aim 4) To investigate the roles of IL-27RA in conventional and unconventional T cells with a mechanistic focus on co-inhibitory/co-stimulatory receptors during lung infection with L. pneumophila and L. longbeachae in mice. In summary, the proposed studies will test the novel concept that IL-27 plays a critical role for the lung host response and outcome of Legionellosis and that IL- 27RA initiates selective programs in NK cells versus T cells.

项目摘要：军团病（军团病）是一种非典型肺炎，发病率急剧上升尽管接受了治疗，美国患者的死亡率仍保持在 3-30% 左右。军团病是由军团菌科的兼性细胞内细菌引起的，这些细菌存在于自然环境中。吸入受污染的气溶胶可能导致感染、病原体逃逸。肺泡巨噬细胞（AM）内含有空泡的军团菌的根除和持续复制。随后的炎症促进骨髓细胞和淋巴细胞浸润到肺部。细胞通过细胞因子相互通讯。白细胞介素 27 (IL-27) 是一种异二聚体细胞因子。 p28 和 EBI3 亚基的非共价相互作用由模式识别受体 (PRR) 诱导。单核吞噬细胞（AM、单核细胞、树突状细胞）中的 IL-27 与其独特受体的连接。淋巴细胞上的 IL-27RA 链启动 STAT1/STAT3 磷酸化，IL-27RA 信号启动多效性。我们初步认为，这些程序首先会加剧急性炎症，然后限制长时间的 T 细胞激活。数据支持这样的新概念：IL-27 是宿主对军团菌感染反应的关键参与者。患有退伍军人病且 IL-27RA 缺乏的人类患者的支气管肺泡灌洗液中的水平升高在此，我们建议检验 IL-27 产生的中心假设。军团菌感染单核吞噬细胞并在淋巴细胞中启动二分程序，包括 NK 细胞的保护性激活和肺部不良 T 细胞介导的免疫抑制。目的 1) 查明。我们的目标是肺单核吞噬细胞亚群内军团菌病期间 IL-27 的细胞来源。评估相关 PRR 免疫传感器对嗜肺军团菌样品诱导 IL-27 的贡献。将研究退伍军人病患者的 IL-27 与 PD-1/PD-L1 轴和可溶性目标 2) 表征组成型 IL-27RA 的功能后果。在感染的 IL-27RA-/- 小鼠中进行消融，并通过单细胞、多维研究宿主反应程序我们还将评估中和 IL-27 抗体和一个蛋白质转录组学 (CITE-Seq/Total-Seq)。设计诱饵受体以改善小鼠肺炎的严重程度目标 3) 根据初步数据，我们的目标是研究 NK 细胞特异性删除 IL-27RA 的新型条件小鼠炎症反应的改变。我们将研究 NK 细胞成熟是否与 IL-27RA 控制的转录开关相关通过参与非 STAT 磷蛋白信号传导来进行程序目的 4) 研究 IL-27RA 在传统和非常规 T 细胞，在机制上侧重于共抑制/共刺激受体小鼠体内嗜肺军团菌和长滩军团菌的肺部感染总之，拟议的研究将测试 IL-27 对军团病的肺宿主反应和结果起着关键作用的新概念，并且 IL- 27RA 启动 NK 细胞与 T 细胞的选择性程序。