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（军团疾病）是一种非典型肺炎的形式，钢升高美国发病率。患者的死亡率停滞在目的地治疗3-30％左右。军团病是由Legionellaceae家族的兼性细胞内细菌引起的，该细菌居住在自然中和设计的水生栖息地。吸入被污染的气溶胶会导致感染，病原体的演变根除肺泡巨噬细胞（AMS）内含水液的军团菌中的根除和连续复制。确保炎症会促进髓样细胞和淋巴细胞浸润到肺中。这些免疫细胞通过细胞因子相互通信。白介素27（IL-27）是由由异二聚体细胞因子形成的亚基P28和EBI3的非共价相互作用。 IL-27是由模式识别受体（PRR）诱导的单核吞噬细胞（AMS，单核细胞，树突状细胞）的激活。 IL-27连接及其独特的接收器链，IL-27RA，淋巴细胞启动STAT1/STAT3磷酸化。 IL-27RA信号传导启动多效性可以首先加剧急性炎症的程序，然后限制延长T细胞激活。我们的初步数据支持新概念，即IL-27是宿主对军团菌感染的反应的关键参与者。 IL-27是人类疾病患者和IL-27RA患者的支气管肺泡灌洗液升高小鼠对感染更具耐药性。在这里，我们建议检验中心假设，即IL-27是由受军团菌感染的单核吞噬细胞并启动淋巴细胞中的二分法程序，其中包括 NK细胞的保护性激活和肺中不良T细胞介导的免疫抑制。目标1）查明肺单核吞噬细胞子集中IL-27的细胞源IL-27的细胞源。评估相关的PRR免疫传感器对肺炎乳杆菌诱导的IL-27的贡献。来自军团疾病患者将研究IL-27与PD-1/PD-L1轴的关联和可溶性免疫病理学标记。目标2）表征本构IL-27RA的功能后果在感染的IL-27RA - / - 小鼠中消融，并通过单维，多维研究宿主响应程序 proteotransscriptomics（cite-seq/total-seq）。我们还将评估中和IL-27抗体和设计的诱饵受体可改善小鼠的肺炎严重程度。目标3）基于初步数据，我们的目标是研究我们新型有条件小鼠的炎症反应改变了IL-27RA的NK细胞特异性缺失。我们将研究NK细胞成熟是否与IL-27RA控制转录的转换有关通过参与非Stat磷蛋白信号传导的程序。目标4）调查IL-27RA在传统和非常规的T细胞，在机械上侧重于共同抑制/共刺激受体。小鼠肺炎和龙乳杆菌感染肺部。总而言之，拟议的研究将测试 IL-27在肺宿主反应和军团菌病的结果中起着关键作用的新颖概念以及IL- 27RA在NK细胞与T细胞中启动选择性程序。