Interleukin-27 in host response to Legionella infection

Interleukin-27 在宿主对军团菌感染的反应中

• 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
• 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' 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

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：军团菌病是一种非典型肺炎，发病率急剧上升。 在美国的发病率。尽管接受了治疗，患者的死亡率仍停留在3%-30%左右。 军团菌病是由军团菌科兼性胞内细菌引起的，这些细菌生活在天然的 以及精心设计的水生栖息地。吸入受污染的气雾剂可导致感染、逃避病原体 在肺泡巨噬细胞(AM)内含有空泡的军团菌中根除和持续复制。 随之而来的炎症促使髓系细胞和淋巴细胞渗入肺部。这些免疫 细胞之间通过细胞因子进行交流。白介素27(IL-27)是一种异二聚体细胞因子，由 P28和EBI3亚基的非共价相互作用。模式识别受体(PRR)诱导IL-27的表达 单核巨噬细胞(AM、单核细胞、树突状细胞)的激活。IL-27与其独特受体的结扎 淋巴细胞上的IL-27RA链启动STAT1/STAT3的磷酸化。IL-27RA信号启动多效性 程序，这可能首先加剧急性炎症，然后限制延长的T细胞激活。我们的预赛 数据支持IL-27是宿主对军团菌感染反应的关键角色这一新概念。IL-27是 退伍军人病伴IL-27RA缺陷患者肺泡灌洗液中IL-27RA水平升高 老鼠对感染的抵抗力更强。在这里，我们建议检验IL-27是由 军团菌感染单核巨噬细胞并启动淋巴细胞的二分性程序，包括 肺组织中NK细胞的保护性激活与T细胞介导的免疫抑制目标1)准确定位 军团菌病时肺单核巨噬细胞亚群中IL-27的细胞来源(S)。我们的目标是 评价相关PRR免疫传感器在嗜肺乳杆菌诱导IL-27中的作用。样品来自 军团病患者将研究IL-27与PD-1/PD-L1轴和可溶性的关系 免疫病理学的标志物。目的2)表征组成性IL-27RA的功能后果 在感染IL-27RA-/-小鼠中进行消融，并用单细胞、多维研究宿主反应程序 蛋白质转录组学(CITE-Seq/Total-Seq)。我们还将评估中和IL-27抗体和 改善小鼠肺炎严重程度的工程诱骗受体。目标3)基于初步数据，我们的目标是 研究具有NK细胞特异性IL-27RA缺失的新型条件性小鼠的炎症反应改变。 我们将研究NK细胞成熟是否与IL-27RA控制的转录开关有关 通过参与非STAT磷蛋白信号转导进行编程。目的：探讨IL-27RA在血管内皮细胞癌中的作用。 常规和非常规T细胞，机械地集中在共抑制/共刺激受体上 嗜肺乳杆菌和长链球菌对小鼠的肺部感染。总括而言，拟议的研究将测试 新的概念，即IL-27在军团菌病的肺宿主反应和转归中起关键作用，并且IL-27 27RA在NK细胞与T细胞之间启动选择性程序。