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：军团病是一种急剧上升的非典型肺炎